Article

Heritabilities of radiologic osteoarthritis in peripheral joints and of disc degeneration of the spine

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Abstract

Objective To estimate the genetic influence on the occurrence of radiologic osteoarthritis (ROA) in the knees, hips, and hands and disc degeneration of the spine in the general population.MethodsA random sample of 1,583 individuals was drawn to estimate the prevalence of ROA and disc degeneration in the general population. Of 118 probands with multiple affected joint sites who were derived from this sample, we were able to recruit 257 siblings. The variance of ROA and disc degeneration within sibling pairs was compared with the variance between sibling pairs. Heritability estimates for ROA in the knees, hips, and hands and for disc degeneration of the spine were calculated. OA was defined according to radiologic criteria, using the Kellgren/Lawrence grading system.ResultsWe observed that hand ROA and disc degeneration of the spine were statistically significantly more frequent in siblings than in the random sample, whereas the prevalence of knee and of hip ROA was similar and lower, respectively. Heritability estimates for hand ROA and disc degeneration were statistically significant, P = 0.56 (95% confidence interval [95% CI] 0.34–0.76) and P = 0.75 (95% CI 0.30–1.00), respectively. For knee and hip ROA, no evidence of a genetic effect in the general population was found. Finally, the heritability estimate for a score that summed the number of joints affected in the knees, hips, hands, and spine was 0.78 (95% CI 0.52–0.98). All heritability estimates were adjusted for age, sex, body mass index, and bone mineral density.Conclusion The present study shows that in the general population, there is a strong genetic effect for hand ROA and disc degeneration of the spine. The findings on the total number of joints affected at multiple sites suggest genetic susceptibility to generalized OA.

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... Increasingly, studies have shown that one of the main symptoms associated with intervertebral disc (IVD) degeneration (IDD) is CLBP (5)(6)(7)(8). A number of researchers have reported that genetic factors accounted for >68% of the pathogenic factors that are associated with IDD, although a variety of factors can lead to IDD (9)(10)(11). IDD is the pathological basis of disc herniation, and it is likely to increase the susceptibility of disc herniation (12,13). ...
... Vascularized IVD tissue not only increases blood circulation and improves the nutrition of NPCs, but also plays an important role in the spontaneous absorption of prolapsed IVD tissue (104,107,112). Neovascularization facilitates the infiltration of inflammatory cells, such as macrophages, into NP tissues (9,112,113). The prolapsed IVD tissue can be phagocytosed by macrophages or dissolved via autoimmune reactions (112,113). ...
... Interestingly, p53-enhanced HIF-1α ubiquitination and degradation is involved in the malfunction of cell mitochondria (119). PHD3 is a critical regulator of HIF-1α, p53 and NF-κB pathways (9,21,118,120). HIF-1α upregulates the expression of PHD3, while PHD3 consolidates the transcriptional activity of HIF-1α (21). PHD3 upregulates the TNF-α-induced NF-κB/p65 signaling activity to reinforce the expression of ADAMTS-5 and MMP-13; additionally it can downregulate the expression of the genes ACAN and COL2 (9,121). ...
Article
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Lower back pain (LBP) is one of the most common reasons for seeking medical advice in orthopedic clinics. Increasingly, research has shown that symptomatic intervertebral disc degeneration (IDD) is mostly related to LBP. This review first outlines the research and findings of studies into IDD, from the physiological structure of the intervertebral disc (IVD) to various pathological cascades. The vicious cycles of IDD are re‑described in relation to the analysis of the relationship among the pathological mechanisms involved in IDD. Interestingly, a 'chief molecule' was found, hypoxia‑inducible factor‑1α (HIF‑1α), that may regulate all other mechanisms involved in IDD. When the vicious cycle is established, the low oxygen tension activates the expression of HIF‑1α, which subsequently enters into the hypoxia‑induced HIF pathways. The HIF pathways are dichotomized as friend and foe pathways according to the oxygen tension of the IVD microenvironment. Combined with clinical outcomes and previous research, the trend of IDD development has been predicted in this paper. Lastly, an early precautionary diagnosis and treatment method is proposed whereby nucleus pulposus tissue for biopsy can be obtained through IVD puncture guided by B‑ultrasound when the patient is showing symptoms but MRI imaging shows negative results. The assessment criteria for biopsy and the feasibility, superiority and challenges of this approach have been discussed. Overall, it is clear that HIF‑1α is an indispensable reference indicator for the accurate diagnosis and treatment of IDD.
... This may reflect several factors including the heterogeneous nature of the disease, the tendency to use less severe phenotypes in genetic searches and the reliance on underpowered studies [13]. Generalized OA-a subtype of primary OA-is characterized by the involvement of multiple joints, and is believed to have a stronger genetic component than individual joint OA [14]. However, genetic data on generalized OA are limited. ...
... Total KL score, osteophyte and JSN scores were used as indicators of the total burden of radiographic OA, which was calculated by summing up the individual scores of each joint. Total radiographic scores have been used by researchers in clinical, biomedical, and genetic studies of OA [14,[27][28][29] as an indicator for total burden of OA. In addition, individuals were evaluated for the criteria required for a diagnosis of generalized OA. ...
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Background A newly-described syndrome called Aneurysm-Osteoarthritis Syndrome (AOS) was recently reported. AOS presents with early onset osteoarthritis (OA) in multiple joints, together with aneurysms in major arteries, and is caused by rare mutations in SMAD3. Because of the similarity of AOS to idiopathic generalized OA (GOA), we hypothesized that SMAD3 is also associated with GOA and tested the hypothesis in a population-based cohort. Methods Study participants were derived from the Chingford study. Kellgren-Lawrence (KL) grades and the individual features of osteophytes and joint space narrowing (JSN) were scored from radiographs of hands, knees, hips, and lumbar spines. The total KL score, osteophyte score, and JSN score were calculated and used as indicators of the total burden of radiographic OA. Forty-one common SNPs within SMAD3 were genotyped using the Illumina HumanHap610Q array. Linear regression modelling was used to test the association between the total KL score, osteophyte score, and JSN score and each of the 41 SNPs, with adjustment for patient age and BMI. Permutation testing was used to control the false positive rate. Results A total of 609 individuals were included in the analysis. All were Caucasian females with a mean age of 60.9±5.8. We found that rs3825977, with a minor allele (T) frequency of 20%, in the last intron of SMAD3, was significantly associated with total KL score (β = 0.14, Ppermutation = 0.002). This association was stronger for the total JSN score (β = 0.19, Ppermutation = 0.002) than for total osteophyte score (β = 0.11, Ppermutation = 0.02). The T allele is associated with a 1.47-fold increased odds for people with 5 or more joints to be affected by radiographic OA (Ppermutation = 0.046). Conclusion We found that SMAD3 is significantly associated with the total burden of radiographic OA. Further studies are required to reveal the mechanism of the association.
... Även de tvillingstudier som undersökt diskdegeneration i nedre delen av ryggen har funnit höga mått på heritabilitet (cirka 70 %) [14,87]. ...
... Likadant var det när man undersökte en grupp med äldre tvillingar (äldre än 70 år)heritabiliteten var mycket låg, och den individuella miljön spelade stor roll för om man hade värk i nacke-skuldror eller inte [44]. När det gäller diskdegeneration i nacken, har studier funnit heritabilitetsmått på cirka 70 procent [14,87]. ...
... 11 Richardson JK Spine 1997 There was a familial predisposition toward lumbar disc pain and injury. 1 2 Matsui H Spine 1998 A family history of operated lumbar disc herniation had a significant implication in lumbar degenerative disc disease. 13 Bijkerk C Arthritis Rheum 1999 There was a strong genetic effect for hand osteoarthritis and disc degeneration of the spine. ...
... Based on the result, they concluded that a family history of operated LDH has a significant implication in LDDs. Bijkerk et al. found that there was a strong genetic effect for LDDg as well as hand osteoarthritis 13) . It has been reported that individuals of Arabic pedigrees 14) with a positive family history were at risk of LDDg, and those from Croatia were also at risk of LDH 15) . ...
Article
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This is a review paper on the topic of genetic background of degenerative disc diseases in the lumbar spine. Lumbar disc diseases (LDDs), such as lumbar disc degeneration and lumbar disc herniation, are the main cause of low back pain. There are a lot of studies that tried to identify the causes of LDDs. The causes have been categorized into environmental factors and genetic factors. Recent studies revealed that LDDs are mainly caused by genetic factors. Numerous studies have been carried out using the genetic approach for LDDs. The history of these studies is divided into three periods: (1) era of epidemiological research using familial background and twins, (2) era of genomic research using DNA polymorphisms to identify susceptible genes for LDDs, and (3) era of functional research to determine how the genes cause LDDs. This review article was undertaken to present the history of genetic approach to LDDs and to discuss the current issues and future perspectives. Fullsize Image
... A normal human intervertebral disc is a fibrocartilaginous structure made of three main components, such as (1) cartilage endplates [6,7]; (2) the annulus fibrosus (AF), composed of type I collagen and fibroblast-like cells [8]; and (3) nucleus pulposus (NP) originated of chondrocyte-like cells [9,10]. Previous studies have found that the inherited factors were directly linked to the pathogenic factors (almost 70%) that were associated with IDD [11][12][13]. Thus, assessing the IDD mechanism from a genetic standpoint is crucial to address the present clinical concerns about chronic LBP. ...
Article
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GINS complex subunit 2 (GINS2) regulates the migration, invasion, and growth of cells in many malignant and chronic diseases. In the present study, we aimed to investigate the expression of GINS2 in the peripheral blood and nucleus pulposus (NP) cells of patients with intervertebral disk degeneration (IDD). GINS2 expression was detected using bioinformatics tools from the GEO public repository and validated using peripheral blood samples from IDD patients and healthy participants. GINS2 clinical significance was explored by the receiver operating curve (ROC) utilizing area under the curve (AUC). Moreover, the influences of GINS2 on cell viability, migration, and invasion were explored by MTT, wound healing, and transwell assays, whereas cell apoptosis was determined by flow cytometry. Expression levels of GINS2 in the peripheral blood were significantly lower in IDD patients than in healthy participants. Moreover, ROC obtained a significantly higher AUC of GINS2 in IDD patients. Further, overexpressed GINS2 increased the proliferation, migration, and invasion of NP cells while overexpressed GINS2 decreased the apoptotic property of cells compared to the NC plasmid and control groups. In conclusion, GINS2 might be a potential therapeutic target of IDD.
... More than 50% of the OA cases can be attributed to genetic factors, demonstrated by twins and family studies [31]. It is suggested that OA of the hand, spine, hip, and knee are all heritable [32]. Recently, genetic studies have found many genes are contributing to OA, although with relatively modest effect [33]. ...
Article
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Background Knee osteoarthritis (OA) is a complex arthritic condition in which genetic factors play an important role. ADAM12 gene is one of the recognized candidate genes although the results are conflicting. To derive a more precise estimation of the association between rs3740199 polymorphism in ADAM12 gene and risk of knee OA, we performed a meta-analysis based on six related studies, including a total of 2185 cases and 3716 controls. Methods A comprehensive search was performed to identify related studies up to April 14, 2017. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Different genetic models were used to assess the pooled and stratified data. Results Overall, no significant association was found in all genetic models (C vs. G, OR = 0.983, 95% CI = 0.910–1.061; CC vs. GG, OR = 1.033, 95% CI = 0.851–1.255; CG vs. GG, OR = 1.030, 95% CI = 0.877–1.209; CC/CG vs. GG, OR = 1.031, 95% CI = 0.886–1.201; CC vs. CG/GG, OR = 1.017, 95% CI = 0.868–1.190). When stratified by ethnicity, no significant association was found. Conclusions This meta-analysis suggested that the rs3740199 polymorphism does not contribute to the development of knee OA. Additional well-designed large studies are required to confirm these findings in different populations.
... OA has been widely considered to be a polygenic disease, having an important hereditary component [25]. Inheritance studies involving family groups and twin pairs have revealed a considerable genetic contribution to the development of OA, with heritability estimates ranging from 39% to 78% at different joints [26][27][28]. ...
Article
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Osteoarthritis (OA) is a major cause of disability in the adult population. As a progressive degenerative joint disorder, OA is characterized by cartilage damage, changes in the subchondral bone, osteophyte formation, muscle weakness, and inflammation of the synovium tissue and tendon. Although OA has long been viewed as a primary disorder of articular cartilage, subchondral bone is attracting increasing attention. It is commonly reported to play a vital role in the pathogenesis of OA. Subchondral bone sclerosis, together with progressive cartilage degradation, is widely considered as a hallmark of OA. Despite the increase in bone volume fraction, subchondral bone is hypomineralized, due to abnormal bone remodeling. Some histopathological changes in the subchondral bone have also been detected, including microdamage, bone marrow edema-like lesions and bone cysts. This review summarizes basic features of the osteochondral junction, which comprises subchondral bone and articular cartilage. Importantly, we discuss risk factors influencing subchondral bone integrity. We also focus on the microarchitectural and histopathological changes of subchondral bone in OA, and provide an overview of their potential contribution to the progression of OA. A hypothetical model for the pathogenesis of OA is proposed.
... An analysis of the individual MRI fi ndings suggested that disc bulging and height were the primary contributors to the genetic determination of the overall score. Bijkerk et al. 26 estimated the genetic infl uence on the occurrence of IDD in a random sample of 1,583 individuals from the general population. They observed that IDD was signifi cantly more frequent in siblings than in the random sample. ...
Article
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Intervertebral disc degeneration (IDD) can contribute to the development of low back pain and acute lumbar radiculopathy. The dramatic change in the concept of risk factors for IDD from one where age and mechanical factors were paramount to the current theory that genetic risk factors are predominant made it important to review the studies of the genetic infl uences on IDD beginning with familial aggregation and heritability estimation and fi nishing with specifi c studies of genes associated with IDD. Methods: Narrative review of English language medical literature. Results and Conclusions: Prior research has demonstrated the existence of familial predisposition to IDD with a heritability range 34-75% in different spine locations. Segregation analysis shows that the mode of inheritance is complex with multiple factors and multiple genes likely involved in intergenerational transmission. There are a number of genes that have been associated with IDD in humans, including genes coding for collagen I, collagen IX (COL9A2 and COL9A3), collagen XI (COL11A2), IL-1, aggrecan, vitamin D receptor, MMP-3, and CILP. For specifi c genes and some environmental factors, gene–gene, gene–environment and gene-age interactions may exist. Candidate-gene association studies have limitations in detecting the genetic basis of the disease because this approach relies on having predicted the correct genes on the basis of biological hypothesis or the location of the known linkage regions. Additional studies, including linkage analyses and whole genome scan studies in different populations and whole range of ages, are required to better understand the infl uence of aforementioned genes on IDD and probably to fi nd new candidate genes. Keywords: intervertebral disc degeneration, heritability, genes, spine
... Sambrook et al. (1999) found overall heritability estimates of 74% for LDD and 73% for CDD. These results were supported by Bijkerk et al. (1999), who found heritability estimates of 75% for multiple intervertebral disc herniations. ...
... In contrast to the relatively minor contribution of these risk factors [10][11][12], twin-pair studies have found a strong familial aggregation and heritability for IDD [13][14][15][16]. In fact, genetic factors account for up to 75% of individual susceptibility to IDD [12,[16][17][18][19]. ...
Article
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Intervertebral disc degeneration (IDD) is the most common diagnosis in patients with back pain, a leading cause of musculoskeletal disability worldwide. Several conditions, such as occupational activities, gender, age, and obesity, have been associated with IDD. However, the development of this disease has strong genetic determinants. In this study, we explore the possible association between rs1800587 (c.-949C>T) of interleukin-1 alpha (IL1A) and rs2228570 (c.2T>V) and rs731236 (c.1056T>C) of vitamin D receptor (VDR) gene polymorphisms and the development of IDD in northwestern Mexican Mestizo population. Gene polymorphisms were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism, in two groups matched by age and gender: patients with symptomatic lumbar IDD (n = 100) and subjects with normal lumbar-spine MRI-scans (n = 100). Distribution of the mutated alleles in patients and controls was 27.0% versus 28.0% (P = 0.455) for T of rs1800587 (IL1A); 53.0% versus 58.0% (P = 0.183) for V of rs2228570 (VDR); and 18.0% versus 21.0% (P = 0.262) for C of rs731236 (VDR). Our results showed no association between the studied polymorphisms and IDD in this population. This is the first report on the contribution of gene polymorphisms on IDD in a Mexican population.
... It has an extremely wide substrate range; it has features of splitting the non-helical region of proteoglycan, laminin, fibronectin casein and collagen (7). It was shown in the literature that other stromelysin group enzymes have increased expression in osteoarthritis patients and also MMP-11 enzyme activity increased in the late stage of the same patients (6). There is no data in the literature regarding a role for it in disc degeneration. ...
Article
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Aim: The intervertebral disc starts to degenerate when a human being begins to stand and learn to walk. It is known that many extrinsic, intrinsic and genetic factors play a role in disc degeneration. In this study, we examined whether the matrix metalloproteinase 11 might be associated with intervertebral disc degeneration. Material and Methods: Fifty-six patients with lumbar disc herniation who were operated at Göztepe Education and Research Hospital Neurosurgery Clinic between September 2008 and December 2009 were prospectively reviewed. History and complaints were obtained from the case reports. Neuroradiological evaluation was performed with magnetic resonance imaging. Surgical findings of cases were reported in the operation notes. Microscopic posterior hemipartial laminectomy and discectomy were performed in all cases. Degenerated herniated disc material of all cases extracted during surgery was evaluated with immunohistochemical staining in Marmara University Neurological Sciences of Medicine, Pathology Laboratory. Results: Comparing the immunohistochemical staining of cases who were 50 years or younger and cases who were over 50 years old, statistical significance was determined. Conclusion: In this study it was shown that matrix metalloproteinase 11 has a role in degenerating intervertebral disc disease but it is not the only factor. Matrix metalloproteinase 11 might be a genetic factor in young-middle aged patients.
... It is known that around 35% of people suffering from OA are occupationally active showing the negative impact of the disease and implications in public health [5,6] . Although OA is considered a disease associated to age, wear and tear of the cartilage of synovial joints have been shown to have a clear genetic component [7] . Hence, the contribution of genetics to OA has been estimated at 65% for knee, 60% for hip and 39% for the hand [8] . ...
Research
Full-text available
Osteoarthritis (OA), the most common form of arthritis around the world, is a multifactorial degenerative joint disorder characterized by articular cartilage degradation, subchondral bone sclerosis, osteophyte formation, synovial membrane inflammation and afection of extraarticular tissue as tendon, ligaments and articular capsule. Although various factors have been recognized as essential in OA development, there is a strong hereditary component and is considered to be a polygenic disease. The identification of genes associated with osteoarthritis can help reveal biological mechanisms that may lead to development of new therapeutic targets or biomarkers for early detection and risk stratification. The goal of this brief review is to offer an overview of the current status of genetics of osteoarthritis.
... In contrast to the relatively minor contribution of these risk factors [10][11][12], twin-pair studies have found a strong familial aggregation and heritability for IDD [13][14][15][16]. In fact, genetic factors account for up to 75% of individual susceptibility to IDD [12,[16][17][18][19]. ...
Article
Full-text available
Intervertebral disc degeneration (IDD) is themost common diagnosis in patients with back pain, a leading cause ofmusculoskeletal disability worldwide. Several conditions, such as occupational activities, gender, age, and obesity, have been associated with IDD. However, the development of this disease has strong genetic determinants. In this study,we explore the possible association between rs1800587 (c.-949C>T) of interleukin-1 alpha (IL1A) and rs2228570 (c.2T>V) and rs731236 (c.1056T>C) of vitamin D receptor (VDR) gene polymorphisms and the development of IDD in northwestern Mexican Mestizo population. Gene polymorphisms were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism, in two groups matched by age and gender: patients with symptomatic lumbar IDD (𝑛 = 100) and subjects with normal lumbar-spine MRI-scans (𝑛 = 100). Distribution of the mutated alleles in patients and controls was 27.0% versus 28.0% (𝑃 = 0.455) for T of rs1800587 (IL1A); 53.0% versus 58.0% (𝑃 = 0.183) for V of rs2228570 (VDR); and 18.0% versus 21.0% (𝑃 = 0.262) for C of rs731236 (VDR). Our results showed no association between the studied polymorphisms and IDD in this population.This is the first report on the contribution of gene polymorphisms on IDD in a Mexican population.
... In agreement with the study results of Hasset [15], the results of our study showed that radiographic OA is a risk factor associated with disc height narrowing. Crosssectional studies have suggested a relationship between disc degeneration and generalized OA [40,41]. Biochemically, it is well known that the components and metabolism of the extracellular matrix of intervertebral discs and articular cartilage share common characteristics. ...
Article
Full-text available
Background The progression of disc degeneration is generally believed to be associated with low back pain and/or degenerative lumbar diseases, especially in the elderly. The purpose of this study was to quantitatively evaluate changes in lumbar disc height using radiographic measurements and to investigate risk factors for development of disc height narrowing of the elderly. Methods From 1997 to 2007, 197 village inhabitants at least 65 years-old who participated in baseline examinations and more than four follow-up examinations conducted every second year were chosen as subjects for this study. Using lateral lumbar spine radiographs of each subject, L1-L2 to L5-S1 disc heights were measured. The subjects were divided into two groups according to the rate of change in disc height: mildly decreased (≤20 % decrease) and severely decreased (>20 % decrease). A stepwise multiple logistic regression analysis was used to select those factors significantly associated with disc height narrowing. Results Disc height at each intervertebral disc (IVD) level decreased gradually over ten years (p < 0.01, an average 5.8 % decrease of all disc levels). There was no significant difference in the rate of change in disc height among the IVD levels. Female gender, radiographic knee osteoarthritis and low back pain at baseline were associated with increased risk for disc height narrowing. Conclusions We conducted the first population-based cohort study of the elderly that quantitatively evaluated lumbar disc height using radiographic measurements. The risk factors identified in this study would contribute to a further understanding the pathology of disc degeneration.
... In a study of recalled physician-diagnosed osteoarthritis, Kujala et al. (1999) found evidence for differences in the aetiology of OA between men and women, with additive genetic effects explaining 44% of variance in women, but non-genetic familial effects explaining 37% of total variance in liability to OA in men. Bijkerk et al. (1999) have also investigated significant evidence of heritability in radiologically determined osteoarthritis of the hand, but failed to find evidence of a genetic effect in the development of OA of the hip or knee. MacGregor et al. (2000) have examined the genetic contribution to radiographic hip OA in women and concluded that the genetic contribution is significant, and accounts for approximately 60% of the variation in population liability to the disease. ...
Article
In order to investigate the genetic and environmental antecedents of osteoarthritis (OA), self-report measures of joint pain, stiffness and swelling were obtained from a popula-tion-based sample of 1242 twin pairs over 50 years of age. In order to provide validation for these self-report measures, a subsample of 118 twin pairs were examined according to the American College of Rheumatology clinical and radiographic criteria for the classification of osteoarthritis. A variety of statistical methods were employed to identify the model derived from self-report variables which would provide optimal prediction of these standardised assessments, and structural equation modelling was used to determine the relative influences of genetic and environmental influences on the development of osteoarthritis. Significant genetic effects were found to contribute to osteoarthritis of the hands, hips and knees in women, with heritability estimates ranging from 30–46% depending on the site. In addition, the additive genetic effects contributing to osteoarthritis in various parts of the body were confirmed to be the same. Statistically significant familial aggregation of osteoarthritis in men was also observed, but it was not possible to determine whether this was due to genetic or shared environmental effects.
... Lumbar disk degeneration tends to be more severe in male patients than in female patients and seems more strongly associated with low back pain, especially in male patients. 5,10 This may partially explain the elevated risk of MSP in all age stratifications in male patients. In addition to social conditioning and psychosocial factors influencing sex differences in pain perception, sex hormones, and different endogenous opioid systems may also play a role. ...
Article
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The aim of the present study was to evaluate the incidence and clinical features of musculoskeletal pain (MSP) in patients with Parkinson's disease (PD) compared to a control group without the disease. The retrospective cohort study used a subset of the Taiwan National Health Insurance Research Database (NHIRD) comprising information on one million beneficiaries randomly sampled from the entire population of Taiwan. A total of 490 patients aged 50 and above with newly diagnosed Parkinson's disease were identified during a period from 2000-2005. Among them, 199 developed MSP following PD. The control group consisted of 1,960 participants without PD over the study period randomly selected by matching PD cases according to the date of PD incidence, age, and sex. The study groups were then followed to the end of 2007. MSP was the end-point. The incidence rate ratios of MSP were higher in the PD group than in the control group, representing an adjusted hazard ratio (AHR) of 1.31 (95% confidence interval [CI] 1.09-1.58). PD was associated with a significantly elevated risk of MSP in all sex and age stratifications, with the highest HR noted for middle-aged male PD patients, followed by older male PD patients. This study showed that the PD may significantly increase the risk of developing MSP. The risk of developing MSP appears to be greatest for middle-aged male PD patients. Clinicians should be more alert for MSP in PD patients and early intervention should be considered .
... Genetics. Although strong evidence for the involvement of genetic factors in structural OA of the hand and the spine exists 42,43 , evidence is inconsistent for knee OA 44 . A metaanalysis 45 showed that not one out of 199 pub lished candidate OA genes has a significant association with knee OA and only two are associated with hip OA. ...
Article
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Osteoarthritis (OA) is the most common joint disorder, is associated with an increasing socioeconomic impact owing to the ageing population and mainly affects the diarthrodial joints. Primary OA results from a combination of risk factors, with increasing age and obesity being the most prominent. The concept of the pathophysiology is still evolving, from being viewed as cartilage-limited to a multifactorial disease that affects the whole joint. An intricate relationship between local and systemic factors modulates its clinical and structural presentations, leading to a common final pathway of joint destruction. Pharmacological treatments are mostly related to relief of symptoms and there is no disease-modifying OA drug (that is, treatment that will reduce symptoms in addition to slowing or stopping the disease progression) yet approved by the regulatory agencies. Identifying phenotypes of patients will enable the detection of the disease in its early stages as well as distinguish individuals who are at higher risk of progression, which in turn could be used to guide clinical decision making and allow more effective and specific therapeutic interventions to be designed. This Primer is an update on the progress made in the field of OA epidemiology, quality of life, pathophysiological mechanisms, diagnosis, screening, prevention and disease management.
... Depending on the joint affected, the heritability of OA is estimated in the range of 40%-60%, 7 8 with hand OA having the largest heritability, that is, ~60%. 9 10 Therefore, in recent years, several large-scale genetic studies have been performed to identify the underlying genes and pathways leading to OA. Multiple significantly associated loci for OA of the hip and knee have been identified through genome-wide association studies (GWAS). ...
Article
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Objective Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. Methods We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. Results We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10⁻¹⁰) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10⁻⁹) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10⁻¹⁵). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10⁻¹⁶). Conclusions Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification.
... Lately, there have been an increasing number of studies examining the association between genetic polymorphisms and the occurrence of OA. Genetic factors have been reported to play a key role in the occurrence of OA. 10 Notably, family and twin studies have shown that genetic factors have a significant influence on more than half of the patients with OA. 11,12 Many genes have been reported to promote the occurrence and development of OA, although the effects were relatively minor. 13 MMP-1 is one such important gene that has been most closely associated with OA. 5,18,19 Recently, multiple studies were conducted to find the association between 1G/2G polymorphism and OA risk 2,14e17 ; however, the results were inconsistent. ...
Article
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Objective The aim of this meta-analysis was to clarify the role of Matrix metalloproteinase 1 (MMP-1) -1607 1G/2G (rs1799750) polymorphism on the osteoarthritis (OA) risk. Methods Articles were selected by retrieving the Web of Science, Embase and Pubmed. The strength of the association between -1607 1G/2G polymorphism and OA risk was assessed by odds ratios (ORs) with the corresponding 95% confidence interval (CI) for each study. Results No significant association between -1607 1G/2G polymorphism and OA risk was found in all the models overall (2G2G vs 1G1G, OR (95%CI) = 0.69 (0.36–1.32), P = 0.54; 2G2G + 2G1G vs 1G1G, OR (95%CI) = 0.88 (0.47–1.63), P = 0.69; 2G2G vs 2G1G + 1G1G, OR (95%CI) = 1.30 (0.68–2.47), P = 0.41; 2 G vs 1G, OR (95%CI) = 0.90 (0.86–1.54), P = 0.66). By subgroup analysis, significant association was found in the “< 60 years” group (2G2G vs 1G1G, OR (95%CI) = 3.46 (2.13–5.62), P = 0.00; 2G2G + 2G1G vs 1G1G, OR (95%CI) = 0.49 (0.31–0.79), P = 0.00; 2G2G vs 2G1G + 1G1G, OR (95%CI) = 2.74 (1.80–4.16, P = 0.00; 2 G vs 1G, OR (95%CI) = 0.56 (0.35–0.89), P = 0.01). Conclusions This meta-analysis showed that -1607 1G/2G polymorphism may increase the susceptibility to OA among the younger populations (<60 years). More studies with detailed information are needed to validate our conclusion. Level of Evidence Level I Diagnostic Study.
... In the past several years, several reports have shown the association between GDF5 gene polymorphisms and the risk of osteoarthritis, congenital dysplasia of the hip. Recently, a number of research groups have reported the GDF5 +104T/C SNP is a protective factor for LDD [12][13][14][15][16][17]. ...
... Además, aunque la OA se considera una enfermedad asociada a la edad, diversos estudios han demostrado que en la etiología existe un claro componente genético; por lo cual se ha estimado que los factores genéticos contribuyen en 65% para la OA de rodilla, 60% para cadera y 39% para la mano. 14,15 Influencia del factor genético en la osteoartrosis La OA se desarrolla como resultado de la interacción de múltiples factores de riesgo, involucrando numerosos trastornos moleculares seguidos de alteraciones anatómicas y fisiológicas. 7 Por esto, es necesario la identificación de los factores de riesgo involucrados para comprender la etio-logía y patogénesis de la OA. 16 Dentro de los factores de riesgo los genéticos siguen siendo desconocidos e incomprendidos; 17,18,19,20 por tanto, es un desafío la identificación de genes o alelos de riesgo que contribuyen en la patogénesis de la OA. ...
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Introduction: The study of our genome has played an important role in the field of personalized medicine and clinical practice becoming a useful tool to assist the medical community in the early diagnosis and treatment of countless diseases; osteoarthritis (OA) is a complex chronic degenerative joint disease, despite the high prevalence of this disease and its great impact on public health, little is currently known about its etiology and risk of progression. The purpose of this review is to show the advances in genetics in the study of osteoartrosis. Methods: The present is a review of the literature of the different aspects in which genetics has developed in the study of osteoartrosis, its scopes and its possible impact on prevention and treatment. Conclusion: The identification of a high number of candidate genes confirms the complex nature of the disease, it seems clear that the degree of expression of different genes is altered between an arthrosic patient and a healthy one. A deeper understanding of the link between the entire genome sequence and the association with well-characterized OA phenotypes will enable the development of biomarkers, report the risk of disease progression and allow better guidance of treatments.
... Además, aunque la OA se considera una enfermedad asociada a la edad, diversos estudios han demostrado que en la etiología existe un claro componente genético; por lo cual se ha estimado que los factores genéticos contribuyen en 65% para la OA de rodilla, 60% para cadera y 39% para la mano. 14,15 Influencia del factor genético en la osteoartrosis La OA se desarrolla como resultado de la interacción de múltiples factores de riesgo, involucrando numerosos trastornos moleculares seguidos de alteraciones anatómicas y fisiológicas. 7 Por esto, es necesario la identificación de los factores de riesgo involucrados para comprender la etio-logía y patogénesis de la OA. 16 Dentro de los factores de riesgo los genéticos siguen siendo desconocidos e incomprendidos; 17,18,19,20 por tanto, es un desafío la identificación de genes o alelos de riesgo que contribuyen en la patogénesis de la OA. ...
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Introducción: El estudio de nuestro genoma ha jugado un papel importante en el campo de la medicina personalizada y la práctica clínica, lo que la convierte en una herramienta útil para ayudar a la comunidad médica en el diagnóstico y tratamiento temprano de innumerables enfermedades. La osteoartrosis (OA) es una enfermedad articular degenerativa crónica compleja; a pesar de su alta prevalencia y gran impacto en la salud pública, actualmente se sabe poco sobre su etiología y riesgo de progresión. El objeto de la presente revisión es mostrar los avances de la genética en el estudio de la osteoartrosis. Métodos: Revisión de la literatura sobre los diferentes aspectos en donde la genética se ha desarrollado en el estudio de la osteoartrosis, sus alcances y sus posibles repercusiones en la prevención y tratamiento. Conclusión: La identificación de un elevado número de genes candidatos nos confirma la compleja naturaleza de la enfermedad, parece claro que el grado de expresión de diferentes genes está alterado entre un paciente artrósico y uno sano. Una comprensión más profunda del vínculo entre la secuencia de todo el genoma y la asociación con fenotipos bien caracterizados de la OA, permitirá el desarrollo de biomarcadores, informar el riesgo de progresión de la enfermedad y permitir una mejor orientación de los tratamientos.
... Bijkerk C et al. reported strong association between OA and genetics. [21] Genetic pathway has been implicated in OA. [22] Current smoking status (OR 0.49 C.I. 0.31-0.78), and current physical activity (OR 0.27 C.I. 0.17-0.43) ...
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Background: Osteoarthritis (OA) is the most common type of arthritis and a very common disease of elderly. It is one of the leading causes of disability. The present study was conducted to estimate the burden of the knee OA among rural elderly. Methods: A community-based cross-sectional study was conducted among 500 randomly selected elderly resident of rural Ballabgarh, Haryana. A semi-structured interview schedule was used by a trained investigator for face-to-face interview, clinical examination of knee using American College of Rheumatology criteria, and quality of life assessment using WHOQOL-BREF. Results: Almost two-third of the participants among 454 elderly recruited, suffered from knee OA (292, 64.3%) had knee OA. History of a knee injury, a family history of knee pain, current physical activity and smoking status were found to be significantly associated with knee OA, in multivariate logistic regression model. Elderly suffering from knee OA had significantly lower quality-of-life scores contrasted to those not (p-value < 0.001). The scores were significantly lower for all the domains (P-value <0.001) among elderly suffering with the knee OA, with the maximum effect seen in psychological, and physical domain. Conclusion: Rural elderly of Ballabgarh, Haryana, had a high burden of knee OA. Elderly suffering from knee OA had significantly lower perception of their quality of life most affected is the psychological and physical domains of quality of life.
... Excessive apoptosis of intervertebral disc cells play an essential role in IDD 7 . Both genetic and environmental factors contribute to the development of IDD, but genetic factors are considered to be the most important contributors [13][14][15][16] . ...
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Intervertebral disc degeneration (IDD) is an important factor leading to low back pain, but the underlying mechanisms remain poorly understood. Compared with normal nucleus pulposus (NP) tissues, the expression of circ-GRB10 was downregulated in IDD. Furthermore, overexpression of circ-GRB10 inhibited NP cell apoptosis. circ-GRB10 could sequester miR-328-5p, which could potentially lead to the upregulation of target genes related to cell proliferation via the ErbB pathway. In conclusion, the present study revealed that circ-GRB10/miR-328-5p/ERBB2 signaling pathway is involved in IDD development, suggesting that circ-GRB10 might be a novel therapeutic target for IDD.
... Bijkerk C et al. reported strong association between OA and genetics. [21] Genetic pathway has been implicated in OA. [22] Current smoking status (OR 0.49 C.I. 0.31-0.78), and current physical activity (OR 0.27 C.I. 0.17-0.43) ...
... Osteoarthritis (OA) is a common joint disease and an important cause of pain and disability in the general population. Genetic factors play an important role in the etiology of various subtypes of OA (1)(2)(3)(4)(5). There has been a large amount of interest in the role of cytokines as mediators of joint damage and inflammation in the pathogenesis of OA. ...
... Increasing evidence has shown that IDD is a multifaceted spinal disease. Both genetic and environmental factors contribute to IDD, but genetic factors are considered to be the greatest contributors [12][13][14][15]. The genetic machinery ranges from single nucleotide variants and coding genes to newly defined noncoding RNAs (ncRNAs). ...
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Background/aims: Low back pain has become one of the most common musculoskeletal diseases in the world. Studies have shown that intervertebral disc degeneration (IDD) is an important factor leading to low back pain, but the mechanisms underlying IDD remain largely unknown. Research over the past decade has suggested critical roles for microRNAs (miRNAs) in natural growth and disease progression. However, it remains poorly understood whether circular RNAs participate in IDD. Methods: Clinical IDD samples were collected from 20 patients who underwent discectomy. Weighted gene co-expression network analysis was used to identify the co-expression miRNA network modules (highly co-expressed clusters of miRNAs) that were associated with IDD grade. Results: miR-3150a-3p was the most significantly up-regulated miRNA in module "Blue." Notably, aggrecan (ACAN) was identified as a direct target gene of miR-3150a-3p and ACAN expression was regulated by miR-3150a-3p. Overexpression of miR-3150a-3p decreased ACAN expression in nucleus pulposus cells, whereas inhibition of miR-3150a-3p increased ACAN expression. In addition, ACAN expression was negatively correlated with IDD grade. Conclusion: Our study suggests that the reduction of ACAN expression induced by the upregulation of miR-3150a-3p might participate in the development of IDD.
... Besides shared environmental factors, intervertebral disc degeneration and OA also share genetic aspects. For example, Bijkerk et al. found a strong genetic effect for intervertebral disc degeneration and hand OA (127), and Loughlin describes several genetic polymorphisms that are attributed to both intervertebral disc degeneration and OA (128). They demonstrate that GDF5 polymorphism rs143383 is a risk factor for both intervertebral disc degeneration and knee OA, just as the repeat polymorphism of the asporin gene (ASPN) (129). ...
Article
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Intervertebral disc degeneration describes the vicious cycle of the deterioration of intervertebral discs and can eventually result in degenerative disc disease (DDD), which is accompanied by low‐back pain, the musculoskeletal disorder with the largest socio‐economic impact world‐wide. In more severe stages, intervertebral disc degeneration is accompanied by loss of joint space, subchondral sclerosis and osteophytes, similar to osteoarthritis in the articular joint. Inspired by this resemblance, we investigated the analogy between human intervertebral discs and articular joints. Although embryonic origin and anatomy suggest substantial differences between the two types of joint, some features of cell physiology and extracellular matrix in the nucleus pulposus and articular cartilage share numerous parallels. Moreover, there are great similarities in the response to mechanical loading and the matrix‐degrading factors involved in the cascade of degeneration in both tissues. This suggests that the local environment of the cell is more important to its behaviour than embryonic origin. Nevertheless, osteoarthritis is widely regarded as a true disease, while intervertebral disc degeneration is often regarded as a radiological finding and degenerative disc disease is undervalued as a cause of chronic low‐back pain by clinicians, patients and society. Emphasizing the similarities rather than the differences between the two diseases may create more awareness in the clinic, improve diagnostics in degenerative disc disease, and provide cross‐fertilization of clinicians and scientists involved in both intervertebral disc degeneration and osteoarthritis. This article is protected by copyright. All rights reserved.
Chapter
Degenerative disk disease (DDD) is a common cause of low back pain (LBP); however, the exact relationship between the two remains unknown. The functional spinal unit (FSU) consisting of an anterior intervertebral disk and two posterior facet joints undergo structural changes as a result of degeneration, which may lead to LBP. Over time we have come to understand that the pathophysiology of DDD is most likely a multifactorial process. Degeneration of the spine is an inevitable consequence of aging and can be due to repetitive biomechanical loading of the spine and genetic predisposition. Clinical presentation is a key to the diagnosis of DDD with the physical exam being an important adjunct in determining discogenic etiology of symptoms. Other disorders may elicit LBP and should be considered during the history and physical examination. Magnetic resonance imaging (MRI) is the gold standard diagnostic tool for the evaluation of DDD. Conservative management is reasonable as majority of these patients recover from their symptoms. The most common surgical interventions involve fusion and more recently artificial total disk replacement (TDR). In addition, each procedure and surgical approach has advantages and disadvantages with associated complications.
Article
Genetics of low back pain have been extensively studied during the past 15 years. In twin studies, heritabilities of degenerative disc disease and of low back pain have been estimated between 29% and 80% and between 21% and 67%, respectively. The familial aggregation of degenerative disc disease may vary between 34% and 61%. A meta-analysis of a genome-wide association study has identified a genetic association with a variant of PARK2 gene. A systematic review of genetic association studies in degenerative disc disease has confirmed a moderate level of evidence for variants of ASPN, COL11A1, GDF5, SKT, THBS2 and MMP9 genes. Several variants of candidate genes coding for structural proteins of the intervertebral disc have been associated with low back pain, in particular ACAN, COL9A2, COL9A3, and ASPN, as well as functional polymorphisms of COL11A1, SPARC, and CILP genes. A genetic association has been reported for alleles coding for catabolic proteins, in particular MMP1 and MMP3. Genes coding for interleukins (IL), in particular the IL1 cluster, for growth factors and for proteins involved in pain, such as COMT, OPRM1 and GCH1, have also been reported. Genome-wide gene expression studies in the annulus have shown an upregulation of pain genes, such as Bradykinin receptor B1 and COMT. Genes of pro-inflammatory cytokines, of chemokines and of extracellular matrix components, have also been differentially expressed. In the nucleus pulposus, moderately affected discs overexpressed ACAN, COL2, SOX9, COL1 genes whereas severely affected discs overexpressed IL-1b and TNFα.
Article
Our aim was to determine whether asporin (ASPN) D-repeat polymorphisms are associated with susceptibility to osteoarthritis (OA). A meta-analysis was conducted to examine the association between the ASPN D14, D13, and D15 alleles and OA of the knee and hip in each ethnic group. In total, 9 studies from eight articles involving 4,417 OA patients and 3,403 controls were considered in the meta-analysis. Meta-analysis showed no association between OA and the ASPN allele coding for 14 D-repeats (D14) in the overall population (OR 1.161, 95 % CI 0.934–1.444, p = 0.178). Stratification by ethnicity identified no association between the ASPN D14 allele and OA in Europeans or Asians (OR 1.035, 95 % CI 0.914–1.173, p = 0.589; OR 1.537, 95 % CI 0.899–2.626, p = 0.116), respectively. However, high heterogeneity was found in Asians (I 2 = 81.2, p = 0.001). Meta-analysis of OA by site showed no association between knee and hip OA and the ASPN D14 allele (OR 1.240, 95 % CI 0.946–1.627, p = 0.119; OR 1.130, 95 % CI 0.767–1.665, p = 0.537). Meta-analysis of D14 versus D13 allele showed the same pattern of OA association as the D14 allele. No association was found between the ASPN D13 and D15 alleles and risk of developing OA by meta-analysis (OR 0.942, 95 % CI 0.840–1.056, p = 0.304; OR 1.050, 95 % CI 0.956–1.154, p = 0.306), respectively. This meta-analysis shows that the ASPN D14, D13, and D15 alleles are not associated with the development of OA in Europeans and Asians. Thus, further study of this relationship is required in homogenous populations because of the heterogeneity of the ASPN D14 allele observed in Asians.
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Low back pain (LBP), which is one of the most severe medical and social problems globally, has affected nearly 80% of the population worldwide, and intervertebral disc degeneration (IDD) is a common musculoskeletal disorder that happens to be the primary trigger of LBP. The pathology of IDD is based on the impaired homeostasis of catabolism and anabolism in the extracellular matrix (ECM), uncontrolled activation of immunologic cascades, dysfunction, and loss of nucleus pulposus (NP) cells in addition to dynamic cellular and biochemical alterations in the microenvironment of intervertebral disc (IVD). Currently, the main therapeutic approach regarding IDD is surgical intervention, but it could not considerably cure IDD. Exosomes, extracellular vesicles with a diameter of 30–150 nm, are secreted by various kinds of cell types like stem cells, tumor cells, immune cells, and endothelial cells; the lipid bilayer of the exosomes protects them from ribonuclease degradation and helps improve their biological efficiency in recipient cells. Increasing lines of evidence have reported the promising applications of exosomes in immunological diseases, and regarded exosomes as a potential therapeutic source for IDD. This review focuses on clarifying novel therapies based on exosomes derived from different cell sources and the essential roles of exosomes in regulating IDD, especially the immunologic strategy.
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This review will acquaint the reader with normal development, structure, and function of the intervertebral disc. The disc is composed of the vertebral endplate, nucleus pulposus, and annulus fibrosus. These three functional components all serve important purposes for health and function of the disc. Nutrition and biomechanics are also discussed. The molecular basis of disc degeneration is reviewed so that biologic approaches to the reversal and or treatment of disc degeneration may be better understood.
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Intervertebral discs are pads of fibrocartilage having the capacity to maintain stability under a wide variety of loading conditions, while permitting intersegmental motion of the spine and showing degenerative and aging changes earlier than any other connective tissue in the body. Disc degeneration may manifest as disc space narrowing, disc bulging, protrusion, extrusion, sequestration, annular tears, reduced signal intensity on magnetic resonance imaging, Schmorl’s nodes and vertebral rim osteophytes. It is believed to be clinically important since disc degeneration has been found to be associated with back pain. This Perspective describes how disc degeneration can be distinguished from normal disc aging and reviews factors associated with intervertebral disc degeneration, with a focus on genetic factors in particular.
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Objective This study evaluated the effectiveness of acupuncture point injection (API) with placental extract on pain reduction and joint function in patients with knee osteoarthritis (OA). Methods Fifty-two patients with knee OA, with an average age of 64, and having a symptom duration of more than 3 months were studied in this report. Placental extract was injected weekly into acupuncture point ST35, BL23, BL24 and BL25 for 5 weeks; 8 mL of placental extract into ST35 on the affected side, and 1 mL of placental extract to BL23, BL24 and BL25 bilaterally. Results After a five-week treatment of API with placental extract, pain was substantially decreased in patients of all Kellgren-Lawrence (KL) grades. Improvement of knee joint swelling was also apparent. Decrease of pain and joint swelling improved daily working productive time among patients of all KL grades. Conclusion Study results imply that API with placental extract is a potentially useful therapy to control pain and maintain joint functions in knee OA patients.
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The Spinal Research Foundation is an international non-profi t organization dedicated to improving spinal health care through research and education. The foundation collaborates with spinal research centers of excellence around the world to prove the success of traditional approaches, as well as develop new techniques and technologies. These results are shared with the medical profession and the general public to improve the overall quality and understanding of optimal spinal health care. Donations to improve the quality of spinal health care in America should be directed to:
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Noninflammatory arthropathy is a major manifestation of a number of genetic disorders. There is a great variety of phenotypes, which present a diagnostic challenge in the clinical setting. In some of these conditions, this arthropathy is generalized, while in others it predominates in the hip joints, with or without significant involvement of the spine. Degenerative osteoarthritis, especially of the weight-bearing joints, is a common complication in a large number of genetic skeletal dysplasias and disorders. This chapter reviews the following hereditary noninflammatory arthropathies, focusing on the most recent genetic linkages: spondyloepiphyseal dysplasia (SED), familial osteoarthropathy with a focus on hand osteoarthritis, primary osteoarthropathy of the hip, and Mseleni joint disease.
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Study design: This is a retrospective case control study. Objective: Identify risk factors and assess their relative impact on the development of degenerative disk disease (DDD). Summary of background data: DDD is responsible for widespread disability in the civilian and military population. Despite the impact of low back pain and DDD, its multifactorial etiology is not entirely understood. Materials and methods: The Defense Medical Surveillance System was searched for military members with the diagnosis of DDD as identified with the use of International Classification of Disease, 9th Revision (ICD-9) codes. These patients were compared with an age-matched and sex-matched control of military members without DDD from the Defense Medical Surveillance System. The prevalence of risk factors (obesity, hip, and knee osteoarthritis, tobacco dependence, diabetes, and type of employment) was then determined for both groups. In total, 160,911 patients with DDD were identified compared with 315,225 controls. Multivariate conditional logistical regression analysis was utilized to determine odds ratio (OR) for these groups based on data matched by age and sex and were adjusted for military rank and race/ethnicity. Results: Diabetes showed an OR of 1.469 [confidence interval (CI), 1.350-1.598]. Hip and knee arthritis produced an OR of 2.925 (CI, 2.685-3.187) and tobacco dependency showed an OR of 1.799 (CI, 1.762-1.836). The comparison of overweight to normal body mass index produced an OR of 1.334 (CI, 1.307-1.361) and the analysis of obese to normal body mass index had an OR of 1.556 (CI, 1.497-1.618). There failed to be a clinically significant association between military duty assignments and the presence of DDD. Conclusions: Our research failed to show a clinical significance association between military duty assignment and DDD. However, we were able to identify a significant association between concomitant hip and knee osteoarthritis, obesity, diabetes, and tobacco dependency with the development of DDD. Level of evidence: Level IV.
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Osteoarthritis (OA) has a genetic component but it is uncertain if the offspring of those with knee OA are at a greater risk. The aim of this study was to describe radiographic OA (ROA) progression and cartilage loss over 10 years in a midlife cohort with some having a family history of OA and some community based controls. 220 participants [mean-age 45(26-61); 57% female] were studied at baseline and ten years. Half were adult offspring of subjects who underwent knee replacement for OA and the remainder were randomly selected controls. Joint space narrowing (JSN) and osteophytes were assessed on radiographs and cartilage volume (tibial, femoral and patellar), cartilage defects, bone marrow lesions and meniscal tears were assessed on MRI. For ROA, there was a significant difference between offspring and controls in unadjusted analysis for change in total ROA, medial JSN, total medial, total lateral and total osteophyte scores. This difference persisted for medial JSN(difference in ratios=+1.93(+1.04,+3.51)) only, after adjustment for confounders and baseline differences. In unadjusted analysis for cartilage loss, offspring lost more cartilage at the medial tibial(difference in means= -79.13(-161.92,+3.71)) site only. This difference became of borderline significance after adjustment for baseline differences (p=0.055). The offspring of subjects having a total knee replacement have a greater worsening of ROA(both JSN and osteophytes) and higher medial tibial cartilage volume loss over ten years. Most of these changes are mediated by differences in baseline characteristics of offspring and controls except for increase in medial JSN. Copyright © 2014. Published by Elsevier Ltd.
Article
Study design: Meta-analysis to collect relevant studies to assess the association between COL11A1 and GDF5 genetic variants and susceptibility to IDD. Objective: To assess whether or not COL11A1 and GDF5 genetic variants were associated with susceptibility to IDD. Summary of background data: IDD or LDH is a major public health problem. There have been several studies evaluating the relationship between COL11A1 and GDF5 genetic variants with risk of IDD. However, the studies were limited in discrete outcome and sample size, and some of the results were contradictory. Methods: We systematically searched the relevant publications in electronic databases. Eligible studies were included based on the defined criteria. The pooled ORs with its 95% CIs were received using STATA 15. Subgroup analysis, sensitivity analysis, publication bias and the "Trim and fill" method were performed in the meta-analysis. Results: A total of 3287 IDD cases and 5115 controls were incorporated into the meta-analysis. Our results demonstrated that COL11A1 rs1676486 was significantly associated with increased IDD susceptibility under all genetic models (allele model T vs C: OR = 1.40, 95% CI 1.23-1.59, P = 0.000; homozygote model TT vs CC: OR = 1.89, 95%CI 1.40-2.56, P = 0.000; dominant model TT+TC vs CC: OR = 1.52, 95%CI 1.29-1.80, P = 0.000; recessive model TT vs TC+CC: OR = 1.58, 95%CI 1.18-2.12, P = 0.002). However, GDF5 rs143383 was not (allele model T vs C: OR = 1.15, 95%CI 0.91-1.44, P = 0.244; homozygote model TT vs CC: OR = 1.22, 95%CI 0.75-2.00, P = 0.429; dominant model TT vs CC+CT: OR = 1.22, 95%CI 0.95-1.57, P = 0.112; recessive model TC+TT vs CC: OR = 1.12, 95%CI 0.73-1.73, P = 0.594). Subgroup analysis indicated ethnicity was not the source of heterogeneity. Sensitivity analysis, publication bias and the "Trim and fill" method demonstrated the meta-analysis was of reliability. Conclusions: Our results suggested that COL11A1 rs1676486 was significantly associated with IDD and the T allele was a risky factor. However, GDF5 rs143383 was not. Level of evidence: 1.
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To assess the potential of studying offspring of people with and without knee osteoarthritis to understand the risk factors and heritability for knee osteoarthritis. We selected two groups of Osteoarthritis Initiative (OAI) participants from one clinical site: (1) participants with bilateral radiographic medial tibiofemoral osteoarthritis and (2) those without tibiofemoral osteoarthritis. We then invited biological offspring ≥ 18 years old to complete an online survey that inquired about osteoarthritis risk factors and symptoms. Among the survey respondents, we recruited ten offspring of members from each group for a clinic visit with bilateral knee posterior-anterior radiographs and magnetic resonance imaging of the right knee. We established contact with 269/413 (65%) eligible OAI participants. Most (227/269, 84%) had ≥ 1 eligible biological offspring, and 213 (94%) were willing to share information about the new family study with their offspring. Our survey was completed by 188 offspring from 110 OAI participants: mean age of 43.0 (10.4) years, mean body mass index of 23.7 (5.9) kg/m², 65% female. Offspring obesity (OR = 2.7, 95% CI 1.0–7.3), hypertension (OR = 3.7, 95% CI 1.2–11.3), and Heberden’s nodes (OR = 3.6, 95% CI 1.0–13.2) were associated with parental osteoarthritis status; however, adjusted models were not statistically significant. Radiographic tibiofemoral osteoarthritis (16/18 knees vs. 2/20 knees) and meniscal abnormalities (7/9 vs. 2/10 index knees) were more common among offspring with parental osteoarthritis status than not. We established the potential of a novel offspring study design within the OAI, and our results are consistent with bilateral radiographic medial tibiofemoral osteoarthritis being a heritable phenotype of osteoarthritis.
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Osteoarthritis, as the most common form of arthritis, affects predominantly middle-aged and elderly population worldwide. This chronic, degenerative, progressive and multifactorial joint disease can affect different joints in the body. One of the most commonly affected joints with osteoarthritis is the hip joint. Hip osteoarthritis is characterized by the presence of pain, stiffness, and limping which ultimately results with inability to perform activities of daily living. Thus, hip osteoarthritis significantly affects patients' quality of life and represents a major public health problem. Because of its high incidence, prevalence and significant medical, social, and economic impact on society as a whole, in this review article we will describe and discuss terminology, classification, epidemiology, etiopathogenesis, clinical presentation, diagnosis, treatment, and prevention of hip osteoarthritis.
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Bioinformatics analysis of published microarray data. This study aimed to reveal the possible genes and pathways related to the pathogenesis of DD by analyzing the microarray data. Disc degeneration (DD) is one of the main causes of low back pain, which has become an enormous economic burden for society. Gene expression data of annulus cells and nucleus pulposus cells from DD patients and controls subjects were downloaded from Gene Expression Omnibus. T-test and enrichment analysis were used to identify differentially expressed genes (DEGs) and DEGs-associated functions and pathways in DD respectively. Protein-protein interaction network and module were constructed to analyze the key nodes associated with this disease. Totally 326 DEGs and 35 DEGs were obtained from the annulus cells and nucleus pulposus cells, respectively. The DEGs of DD in annulus cells were mainly involved in translation, cell adhesion, cell death regulation and skeletal system development whilst the DEGs in nucleus pulposus cells were mainly related to the biological processes of vascular system development, skeletal system development and enzyme-linked receptor protein signaling pathway. COL3A1 was the common DEGs in both annulus cells and nucleus pulposus cells. The ribosomal proteins (RPL8, RPS16 and RPS23) in module were enriched in biological processes of translation, translation elongation and RNA processing. The results revealed the involvement of COL3A1 in skeletal system process and RPL8, RPS16 and RPS23 in the protein synthesis processes in the progression of DD, suggesting their potential use in the diagnosis and therapy of DD.
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The relative importance of genetic factors in determining bone mass in different parts of the skeleton is poorly understood. Lumbar spine and proximal femur bone mineral density and forearm bone mineral content were measured by photon absorptiometry in 38 monozygotic and 27 dizygotic twin pairs. Bone mineral density was significantly more highly correlated in monozygotic than in dizygotic twins for the spine and proximal femur and in the forearm of premenopausal twin pairs, which is consistent with significant genetic contributions to bone mass at all these sites. The lesser genetic contribution to proximal femur and distal forearm bone mass compared with the spine suggests that environmental factors are of greater importance in the aetiology of osteopenia of the hip and wrist. This is the first demonstration of a genetic contribution to bone mass of the spine and proximal femur in adults and confirms similar findings of the forearm. Furthermore, bivariate analysis suggested that a single gene or set of genes determines bone mass at all sites.
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To assess the relative contribution of genetic and environmental factors to common forms of osteoarthritis of the hands and knees. Classic twin study with unselected twins who were screened radiologically for osteoarthritis. 130 identical and 120 non-identical female twins aged 48-70 recruited from a London based twin register and through a national media campaign. Similarity in identical compared with non-identical twin pairs for radiographic changes at the interphalangeal and first carpometacarpal joints of the hands and the tibiofemoral joint and patellofemoral joint of the knee expressed as intraclass correlations. The intraclass correlations of radiographic osteophytes and narrowing at most sites and the presence of Heberden's nodes and knee pain were higher in the identical pairs. The intraclass correlation of the total radiographic osteoarthritis score in identical pairs (rMZ) was 0.64 (SE 0.05) compared with 0.38 (0.08) in non-identical pairs. The proportion of genetic variance of total osteoarthritis score (osteophytes and narrowing) with modelling techniques was estimated at 0.54 (95% confidence interval 0.43 to 0.65) and ranged from 0.39 to 0.65 for different sites and features (p < 0.001) after adjustment for age and weight. These results demonstrate for the first time a clear genetic effect for radiographic osteoarthritis of the hand and knee in women, with a genetic influence ranging from 39-65%, independent of known environmental or demographic confounders. The results of this study should lead to further work on isolating the gene or genes involved in the pathogenesis of the common disabling disease.
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Namaqualand spondyloepiphyseal dysplasia (NSED) is a mild autosomal dominant form of spondyloepiphyseal dysplasia in which changes are maximal in the femoral capital epiphyses and the vertebral bodies. The condition is present in a large multigeneration South African family, and it is clinically important by virtue of severe progressive degenerative osteoarthropathy of the hip joint, which frequently necessitates prosthetic joint replacement in adulthood. Linkage studies using molecular markers have shown that the loci for the NSED and type II collagen genes are linked (LOD score 7.98 at a recombination fraction of .00).
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In this paper the Rotterdam Elderly Study is presented. The aim of the study is to investigate determinants of disease occurrence and progression in the elderly. In addition to contributing to our understanding of the etiology of geriatric illnesses, the study is expected to lead to specific recommendations for intervention. The study focusses on causally related determinants of major diseases in the elderly. Fields of interest for the Rotterdam Elderly Study are- conditions which interfere the most with the quality of life for the elderly. The aims of the Rotterdam Elderly Study are:(1) To investigate, by means of epidemiologic, clinical and basic research, the determinants of diseases in order to assess their etiologic significance. (2) To investigate potentially modifiable determinants in order to be able to develop preventive strategies by providing specific recommendations for intervention studies. The Rotterdam Elderly Study focusses on four primary areas of research: neurogeriatric diseases, cardiovascular diseases, locomotor diseases and ophthalmologic diseases. It is a prospective follow-up study, in which determinants of disease and determintants of progression of disease will be investigated in the total population of 55 years or over of the district of Ommoord in Rotterdam. It is anticipated that about 1–0,000 people will participate in the study and they will be examined in the period of 1991 to 1995.
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In this cross-sectional study, bone mineral density (BMD) measurements were performed in 1762 ambulatory subjects (678 men and 1084 women) aged 55 years and over from the Rotterdam Study, a population based study of diseases in the elderly. BMD measurements of the proximal femur and lumbar spine were performed using dual energy X-ray absorptiometry. No age-related decline in BMD could be observed in the lumbar spine. Yearly percentage BMD reduction in women and men was -0.6% and -0.3% in the femoral neck, -0.8% and -0.5% in the Ward's triangle, and -0.4% and -0.3% in the trochanter, respectively. Late menopause was associated with high BMD in Ward's triangle and lumbar spine. We conclude that: (1) accurate assessment of age-related bone reduction in the spine is impossible from cross-sectional studies since BMD measurements in the elderly may be influenced by spinal osteoarthritis; and (2) the rate of age-related bone reduction in the femoral neck appears to be approximately two times higher in women than in men.
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To investigate the relationship of osteoarthritis (OA) to bone mineral density (BMD) and rate of bone loss. The study group consisted of 2,745 persons (1,624 women) from the general elderly population. Disability was assessed by the Health Assessment Questionnaire. Femoral neck BMD was measured at baseline and, in 1,723 subjects, after 2 years of followup. Knee and hip radiographic OA was assessed on anteroposterior radiographs. With the exception of knee radiographic OA in men, radiographic OA was associated with significantly increased BMD (3-8%). BMD increased significantly according to the number of affected sites and the Kellgren score. Radiographic OA was also associated with significantly elevated bone loss with age (in men, only for radiographic OA of the hip). A significant increase in relation to the number of affected sites and the Kellgren score (except with regard to knee OA in men) was found, independent of disability. Radiographic OA is associated with high BMD and increased rate of bone loss. This suggests a more pronounced difference in BMD earlier in life.
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Likelihood calculation for pedigrees is complicated and often time-consuming. Testing correlation structures due to familial aggregation is therefore a preliminary procedure. A score statistic is given to check correlations between relatives of randomly chosen pedigrees. This statistic can be used for quantitative and dichotomous data. For both data types, the distribution of the statistic under the null hypothesis is derived. To demonstrate the performance of the statistic, results of simulations under various models are given. Finally, the test is applied to data on a continuous blood factor.
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Type II collagenopathies consist of chondrodysplasias ranging from lethal to mild in severity. A large number of mutations has been found in the COL2A1 gene. Glycine substitutions have been the most common types of mutation. Genotype-phenotype correlations in type II collagenopathies have not been established, partly because of insufficient clinical and radiographic description of the patients. We found a glycine-to-arginine substitution at position 154 in type II collagen in two unrelated isolated propositi with spondyloepimetaphyseal dysplasia and provide a comparative clinical and radiographic analysis from birth to young adulthood for this condition. The clinical phenotype was disproportionate short stature with varus/valgus deformities of the lower limbs requiring corrective osteotomies, and lumbar lordosis. The skeletal radiographs showed an evolution from short tubular bones, delayed epiphyseal development, and mild vertebral involvement to severe metaphyseal dysplasia with dappling irregularities, and hip "dysplasia." The metaphyseal abnormalities disappeared by adulthood.
Article
Transgenic mice expressing mutant alpha 1(IX) collagen were produced and found to develop progressive joint degeneration with age, as well as accelerated intervertebral disc degeneration. Radiological and histological studies showed that cervical and lumbar disc degeneration was more advanced in the transgenic mice than in control litter-mates. The changes included shrinkage or disappearance of the nucleus pulposus, and fissures in the annulus fibrosus which sometimes lead to herniation of disc material and slight osteophyte formation. These findings suggest that mutations of the type IX collagen may cause certain forms of degenerative disease in the spine as well as in joints.
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To investigate the inheritance of generalized osteoarthritis (OA). OA was identified on hand and knee radiographs obtained from members of the Framingham Study cohort (the parents) in 1967-1970 and 1992-1993, and from their adult children in the Framingham Offspring Study in 1993-1994. All hand and knee radiographs evaluated for OA were graded using the Kellgren and Lawrence (K/L) scale. A measure of generalized OA was defined as the count of the number of hand and knee joints affected, as determined by the proportion of joints with a K/L grade > or =2. The OA count, treated as a continuous variable, was adjusted for age, body mass index, and a measure of physical activity for each joint area (hand or knee). Calculations were made separately for each generation and each sex, and correlations were analyzed against the standardized residual of OA. Segregation analysis was used to test whether OA aggregated in families, and if its transmission fit a Mendelian pattern. A total of 337 nuclear families with 2 parents and at least 1 biologic offspring were studied. In parents, the mean age was 61.2 years at the time of hand radiographs and 72.8 years at the time of knee radiographs, which were mostly obtained at a later examination. The mean age at the time of radiographs in offspring was 53.9 years. Using standardized residuals, parent-offspring and sibling-sibling correlations ranged from 0.115 to 0.306. In segregation analyses, models testing the hypotheses of no familial aggregation, no familial transmission, or a Mendelian gene alone were all rejected (P < 0.001 for each of these models). The best-fitting models were mixed models with a Mendelian mode of inheritance and a residual multifactorial component. The Mendelian recessive model provided the best fit. These analyses support a significant genetic contribution to OA, with evidence for a major recessive gene and a multifactorial component, representing either polygenic or environmental factors.
Article
To evaluate the familial aggregation of osteoarthritis (OA) in a cohort of healthy volunteers drawn from a community setting. Hand radiographs obtained between 1978 and 1991 and bilateral standing knee radiographs obtained between 1984 and 1991 were read for changes of OA, using Kellgren-Lawrence (K-L) scales. The hand sites were distal interphalangeal (DIP) joints, proximal interphalangeal (PIP) joints, and first carpometacarpal (CMC1) joints. For each joint group, the presence of OA in at least 1 joint in a joint group, the number of affected digits in each joint group, and the sum of the K-L grade across all joints were analyzed. Polyarticular OA was recorded if there were OA findings in 2 of 3 hand joint groups plus 1 or both knees. Data from 167 families with hand radiographs, 157 families with knee radiographs, and 148 families with both hand and knee radiographs were analyzed for sib-sib correlations. After adjustment for age, sex, and body mass index, clinically relevant sib-sib common correlations were found for OA of the DIP, PIP, and CMC1 joints, for OA at 2 or 3 hand sites, and for polyarticular OA (r = 0.33-0.81) when OA was defined according to the number of affected joints or as the sum of the K-L grade across all joints. These results from a cohort of volunteers drawn from a community setting and ascertained without regard to OA status demonstrate familial aggregation of OA and contribute to the evidence for heritability of OA.
Article
A preliminary data set is analysed containing filaria specific IgG4 and IgE levels and the presence of microfilariae of 196 people from families of a village in Indonesia. Since filaria infected people may not be microfilaria positive, a filaria infection can easily be missed. First, the probabilities of a filaria infection are estimated from the IgG4 levels and the presence of microfilariae using the EM algorithm. By dichotomizing these probabilities, infection status is estimated for each person. Then for IgG4, IgE and infection status, the correlations between observations are modelled. Three causes for a correlation are considered, namely genetic, intra-uterine or environmental effects. The correlation structure of the genetic and the intra-uterine effects are quite similar and consequently it may be difficult to disentangle them. Empirical variograms are plotted and the various variance components are estimated by maximizing the log-likelihood. For infection status an environmental effect is found and for IgG4 and IgE levels genetic effects are found.
Article
Epidemiologic studies of rheumatic diseases can be broadly divided into those that describe the occurrence of specific disorders, those that attempt to quantify the role of putative risk factors for disease occurrence, and those that define the outcome and factors associated with it. Studies in this area have tended to be hypothesis testing rather than generating new etiologic or related hypotheses. In contrast to many previously published studies, more recent work has been both substantive in size and focused more on true community-based studies with the consequence that estimates of occurrence in risk obtained are likely to reflect more accurately the true nature of any associations observed.
The epidemiology of chronic rheumatism. Vol. II. Atlas of standard radiographs of arthritis
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