No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Specific bioactive collagen peptides (PETAGILE®) as supplement for horses with osteoarthritis: A two‐centred study
... Lameness and flexion pain improved. Horse Dobenecker et al. [148] (continued on next page) chondrocyte proliferation which contributes to improved availability of type II collagen. The authors also observed that the soy peptide inhibited the expressions of MMP-3, MMP-13, TIMP-1, and TIMP-2 [127]. ...
... Other researchers mixed collagen hydrolysate with the extracts of green tea and curcuminoids just to observe a pain reduction in the treated dogs with RA [146]. In a later study, Dobenecker et al. [148] mixed multifarious peptides obtained from type I collagen and administered them to horses that suffered from arthritis at 50 g/day for 6 weeks. The researchers observed that both flexion pain and lameness were significantly alleviated in the horses. ...
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects the joints of the human body and is projected to have a prevalence age-standardized rate of 1.5 million new cases worldwide by 2030. Several conventional and non-conventional preventive and therapeutic interventions have been suggested but they have their side effects including nausea, abdominal pain, liver damage, ulcers, heightened blood pressure, coagulation, and bleeding. Interestingly, several food-derived peptides (FDPs) from both plant and animal sources are increasingly gaining a reputation for their potential in the management or therapy of RA with little or no side effects. In this review, the concept of inflammation, its major types (acute and chronic), and RA identified as a chronic type were discussed based on its pathogenesis and pathophysiology. The conventional treatment options for RA were briefly outlined as the backdrop of introducing the FDPs that potentiate therapeutic effects in the management of RA.
... We analyzed structure-function relationships and focused on molecular modeling calculations that would allow us to better understand the details of intermolecular interactions between sialic acids and relevant proteins. The collagen hydrolysate under study [32][33][34][35][36][37] was examined with high resolution NMR experiments, especially, DOSY NMR [4,7]. Additionally, molecular modeling approaches such as molecular docking and molecular dynamics simulations were carried out in order to obtain more information about the interaction potency of collagen fragments and sulfated GlcNAc with receptor structures. ...
... The impact of drugs and nutritional supplements on the mobility of randomly selected dogs of the study (Table 3) was evaluated and documented by video at both the beginning and end of the therapy. Our current observations are in full agreement with a horse-study recently published [35]. Representative videos (mp4 format) for two patients from the sulfated glucosamine group, two from the collagen hydrolysate group and one dog from the control group are available for download from the Supplementary Material. ...
Osteoarthritis belongs to the most common joint diseases in humans and animals and shows increased incidence in older patients. The bioactivities of collagen hydrolysates, sulfated glucosamine and a special fatty acid enriched dog-food were tested in a dog patient study of 52 dogs as potential therapeutic treatment options in early osteoarthritis. Biophysical, biochemical, cell biological and molecular modeling methods support that these well-defined substances may act as effective nutraceuticals. Importantly, the applied collagen hydrolysates as well as sulfated glucosamine residues from marine organisms were strongly supported by both an animal model and molecular modeling of intermolecular interactions. Molecular modeling of predicted interaction dynamics was evaluated for the receptor proteins MMP-3 and ADAMTS-5. These proteins play a prominent role in the maintenance of cartilage health as well as innate and adapted immunity. Nutraceutical data were generated in a veterinary clinical study focusing on mobility and agility. Specifically, key clinical parameter (MMP-3 and TIMP-1) were obtained from blood probes of German shepherd dogs with early osteoarthritis symptoms fed with collagen hydrolysates. Collagen hydrolysate, a chondroprotective food supplement was examined by high resolution NMR experiments. Molecular modeling simulations were used to further characterize the interaction potency of collagen fragments and glucosamines with protein receptor structures. Potential beneficial effects of collagen hydrolysates, sulfated glycans (i.e., sulfated glucosamine from crabs and mussels) and lipids, especially, eicosapentaenoic acid (extracted from fish oil) on biochemical and physiological processes are discussed here in the context of human and veterinary medicine.
... We analyzed structure-function relationships and focused on molecular modeling calculations that would allow us to better understand the details of intermolecular interactions between sialic acids and relevant proteins. The collagen hydrolysate under study [32][33][34][35][36][37] was examined with high resolution NMR experiments, especially, DOSY NMR [4,7]. Additionally, molecular modeling approaches such as molecular docking and molecular dynamics simulations were carried out in order to obtain more information about the interaction potency of collagen fragments and sulfated GlcNAc with receptor structures. ...
... The impact of drugs and nutritional supplements on the mobility of randomly selected dogs of the study (Table 3) was evaluated and documented by video at both the beginning and end of the therapy. Our current observations are in full agreement with a horse-study recently published [35]. Representative videos (mp4 format) for two patients from the sulfated glucosamine group, two from the collagen hydrolysate group and one dog from the control group are available for download from the Supplementary Material. ...
The bioactivities of collagen-hydrolysates, sulfated glucosamine and a special fatty acid enriched dog-food were tested in a dog patient study as potential therapeutic treatment options in early osteoarthritis. Biophysical, biochemical, cell biological and molecular modeling methods support that these well-defined substances may act as effective nutraceuticals. Importantly, the applied collagen-hydrolysates as well as sulfated glucosamine residues from marine organisms were strongly supported by both an animal model and molecular modeling of intermolecular interactions. Molecular modeling of predicted interaction dynamics were evaluated for the receptor proteins MMP-3 and ADAMTS-5. These proteins play a prominent role in the maintenance of cartilage health as well as innate and adapted immunity. Nutraceuticals data were generated in a veterinary clinical study focusing on mobility and agility. Specifically, key clinical parameters were obtained from blood probes of German shepherd dogs with early osteoarthritis symptoms fed with collagen-hydrolysates or sulfated glucosamines. Collagen-hydrolysate, a chondroprotective food supplement was examined by high resolution NMR experiments. Molecular modeling simulations were used to further characterize the interaction potency of collagen-fragments and glucosamines with protein receptor structures. Potential beneficial effects of collagen-hydrolysates, sulfated glycans (i.e. sulfated glucosamine from crabs and mussels) and lipids, especially, eicosapentaenoic acid (extracted from fish oil) on biochemical and physiological processes are discussed here in the context of human and veterinary medicine.
... It is thought that in order to exert their biological activity, the shorter sequences of the bioactive peptides must be released from the larger protein structure by enzymatic or chemical treatment prior to oral administration (Möller, Scholz-Ahrens, et al. 2008;Rinaldi et al. 2015;Virgilio 2019). In humans and horses with OA, orally administered CH exerted positive clinical effects on joint pain on patient reported outcomes and orthopaedic examination (Dobenecker et al. 2018;Honvo et al. 2020). Several studies have investigated the clinical effects of CH in dogs with OA (Table 1) (Beynen et al. 2010;Comblain et al. 2017;Dobenecker et al. 2024;Eckert et al. 2021;Schunck, Louton, and Oesser 2017). ...
Osteoarthritis (OA) is a common disease in dogs with severe impact on their welfare. The multimodal management of OA includes feeding therapeutic diets and nutraceuticals to slow down OA progression. Collagen hydrolysates (CH) are a nutritional supplement that may exert anabolic effects on osteoarthritic joint cartilage as well as disease-modifying effects. After oral intake, CH is absorbed, mainly as amino acids, di- and tripeptides that are transported amongst others to the joint. In addition to reducing cartilage degradation, CH metabolites may reduce synovial inflammation and subchondral bone sclerosis during OA. Preliminary evidence in dogs suffering from the consequences of OA support the clinical efficacy of CH with reported reductions in lameness. However, effects on biomarker level of cartilage metabolism and inflammation are inconclusive. Additionally, current studies show a lack of standardised dosing regimens and the use of not validated outcomes. Future work should therefore elucidate further on the bioavailability of CH in dogs in order to establish adequate dosing recommendations. Furthermore, high-quality placebo-controlled randomised controlled trials are essential to dstudies have evaluated the cetermine the clinical efficacy of CH to reduce lameness, prevent OA progression and thereby improve the level of evidence.
... The mixture of various collagen peptides generated from type I collagen showed promising effects in alleviating symptoms of naturally occurring osteoarthritis in horses. Lameness and flexion pain of these horses were significantly improved after oral administration of 50 g of these peptides per day for 6 weeks (Dobenecker et al., 2018). Bovine type I collagen hydrolysate <3 kDa induced type-II and inhibited type-I collagen deposition in interleukin-1β (IL-1β) treated chondrocytes, which was not associated with the expression of metalloproteinases (De Luca et al., 2019), but the exact underlying mechanism was not clarified in this study. ...
Background
Bioactive peptides from different food protein have been reported to have a lot of biological activities, such as anti-inflammation and anti-oxidation, making them beneficial for chronic disease. Osteoarthritis (OA) is one of the major diseases affecting human health worldwide. The main treatment methods of OA are physiotherapy, medication and surgery. Many drug, such as adrenocortical hormone, have serious side effects on the patients. Therefore, it is necessary to search for treatment with less side effects. Recently, biologically active peptides from natural foods have been extensively reported to show beneficial effects on alleviating symptom of osteoarthritis, which make it potential for industrial application in the functional foods.
Scope and approach
In this review, we focus on biological characteristics of food-derived peptides, especially their therapeutic effect in osteoarthritis, and the underlying mechanism by which these peptides exert the biologically function in osteoarthritis.
Key findings and conclusions
Peptides from bovine, chicken, deer are the predominant species for improvement of osteoarthritis in in vitro, in vivo and clinical studies. Marine food is another important protein source for production of bioactive peptide that showed beneficial effect in the treatment of osteoarthritis. A few peptides from plant protein such as soybean also showed positive effect on chondrocytes. However, many bioactive peptides that showed the beneficial effect on osteoarthritis were in the form of mixture. Finding out the exact peptide that exerts the positive effect in the osteoarthritis is necessary for the industrial application in the future.
... Collagen peptides had an anti-inflammatory effect by reducing prostaglandin E2 than the placebo group. Surprisingly, the horses treated with collagen peptides improved movement and willingness to run than the placebo group [137,138]. ...
In biology, collagen-biomaterial regulates several signaling mechanisms of bone and immune cells involved in tissue repair and any imbalance in collagen turnover may affect the homeostasis of cells, becoming a major cause of several complications. In this case, the administration of oral collagen may play a potential role in returning cells to their normal function. For several decades, the beneficial effects of collagen have been explored widely, and thus many commercial products are available in cosmetics, food, and biomedical fields. For instance, collagen-based-products have been widely used to treat the complications of cartilage-related-disorders. Many researchers are reporting the anti-arthritogenic properties of collagen-based materials. In contrast, collagen, especially type-II collagen (CII), has been widely used to induce arthritis by immunization in an animal-model with or without adjuvants, and the potentially immunogenic-properties of collagen have been continuously reported for a long time. Additionally, the immune tolerance of collagen is mainly regulated by the T-lymphocytes and B-cells. This controversial hypothesis is getting more and more evidence nowadays from both sides to support its mechanism. Therefore, this review links the gap between the arthritogenic and anti-arthritogenic effects of collagen and explored the actual mechanism to understand the fundamental concept of collagen in arthritis. Accordingly, this review opens-up several unrevealed scientific knots of collagen and arthritis and helps the researchers understand the potential use of collagen in therapeutic applications.
... All 28 horses, (16 received 25 g/day and 12 received 50 g/day of PENTAGILE), improved their mobility and showed increased willingness to run when compared to the placebo group. The higher dosage (50 g) supplementation was concluded to be more effective and promising enough to further test in longer term studies [51]. ...
Purpose of Review
Osteoarthritis (OA) is the most common forms of arthritis in the general population, accounting for more pain and functional disability than any other musculoskeletal disease. There are currently no approved disease modifying drugs for OA. In the absence of effective pharmacotherapy, many patients with OA turn to nutritional supplements and nutraceuticals, including collagen derivatives. Collagen hydrolyzates and ultrahydrolyzates are terms used to describe collagens that have been broken down into small peptides and amino acids in the presence of collagenases and high pressure.
Recent Findings
This article reviews the relevant literature and serves as a White Paper on collagen hydrolyzates and ultrahydrolyzates as emerging supplements often advertised to support joint health in OA. Collagen hydrolyzates have demonstrated some evidence of efficacy in a handful of small scale clinical trials, but their ability to treat and reverse advanced joint disease remains highly speculative, as is the case for other nutritional supplements.
Summary
The aim of this White Paper is to stimulate research and development of collagen-based supplements for patients with OA and other musculoskeletal diseases at academic and industrial levels. This White Paper does not make any treatment recommendations for OA patients in the clinical context, but simply aims to highlight opportunities for scientific innovation and interdisciplinary collaboration, which are crucial for the development of novel products and nutritional interventions based on the best available and published evidence.
... Some evidence demonstrates that collagen peptides have the effect of preventing and treating osteoarthritis (Table 4). For example, Oral specific collagen peptides (PETAGILEV R ), gelatin hydrolyzed peptides, skin collagen peptides, a combined injection of collagen tripeptide, and hyaluronan (HA) have shown relieving effects on animal arthritis (Dobenecker et al. 2018;Isaka et al. 2017;Naraoka et al. 2013). The probable mechanism involved in the collagen peptides providing relief in osteoarthritis is as follows: 1) collagen peptides promote the synthesis of type II collagen in chondrocytes (Naraoka et al. 2013); 2) collagen peptides inhibit the expression of matrix metalloproteinase-13 (MMP-13) and the degeneration of type II collagen (Isaka et al. 2017); 3) oral collagen peptides also reduce the cartilage inflammatory response, which is related to the reduction of cartilage oligomeric matrix protein (COMP), interleukin-1 (IL-1), and tumor necrosis factor-a (TNF-a) levels (Hong et al. 2019). ...
In 2020, the world’s food crisis and health industry ushered into a real outbreak. On one side, there were natural disasters such as the novel coronavirus (2019-nCoV), desert locusts, floods, and droughts exacerbating the world food crisis, while on the other side, the social development and changes in lifestyles prompted the health industry to gradually shift from a traditional medical model to a new pattern of prevention, treatment, and nourishment. Therefore, this article reviews animal by-products collagen and derived peptide, as important components of innovative sustainable food systems. The review also considered the preparation, identification, and characterization of animal by-product collagen and collagen peptides as well as their impacts on the food system (including food processing, packaging, preservation, and functional foods). Finally, the application and research progress of animal by-product collagen and peptide in the food system along with the future development trend were discussed. This knowledge would be of great significance for a comprehensive understanding of animal by-product collagen and collagen peptides and would encourage the use of collagen in food processing, preservation, and functional foods.
... It has also been reported peptides with antifreezing and cryoprotecting activities are useful in the food industry and in biomedicine [23,24]. Another interesting application of antiarthritic peptides is their use in medicine and veterinary [25,26,27]. ...
Background
Collagen is the most abundant protein in animals and can be obtained from residues of the food industry. Its hydrolysate has many desirable properties that make it suitable as an additive in foods and cosmetics, or as a component of scaffold materials to be used in biomedicine.
Results
We report here the characterization of type I collagen from five different sources, namely bovine, porcine, chicken, trout and salmon, as well as their hydrolysates by means of bioinformatics tools. As expected, the results showed that bovine and porcine collagen, as well as trout and salmon collagen, can be used interchangeably due to their high identity. This result is consistent with the evolution of proteins with highly identical sequences between related species. Also, 156 sequences were found as potential bioactive peptides, 126 from propeptide region and 30 from the central domain, according to the comparison with reported active sequences.
Conclusions
Collagen analysis from a bioinformatic approach allowed us to classify collagen from 5 different animal sources, to establish its interchangeability as potential additive in diverse fields and also to determine the content of bioactive peptides from its in silico hydrolysis.
How to cite
Nuñez SM, Guzmán F, Valencia P, et al. Collagen as a source of bioactive peptides: a bioinformatics approach. Electron J Biotechnol 2020; 48. https://doi.org/10.1016/j.ejbt.2020.09.009.
... Many kinds of food derived bioactive peptides were previously isolated and reviewed (Chakrabarti et al. 2014;Maqsoudlou et al. 2019;Pessione and Cirrincione 2016;Marcone et al. 2017). Many of these peptides were found to have certain effects on human health, in many clinical trials (Hill and Newburg 2015;Akazawa et al. 2008;Dobenecker et al. 2018). Proteins obtained from major food materials were considered safe based on a history of consumption for a long period of time without any adverse effects, and advantageous due to their low cost and stable supply. ...
Various peptides with inhibitory activity against human dipeptidyl peptidase-IV (hDPP-IV), which degrades glucagon-like peptide 1 (GLP-1) and decreases insulin release, were isolated from synthetic tripeptide mixtures, having sequences Val-Pro-Xaa (VPX) or Ile-Pro-Xaa (IPX). All peptides isolated by reversed-phase high performance liquid chromatography (HPLC) analysis were measured for hDPP-IV inhibitory activity. VPV and VPI prepared from the VPX mixture and IPI isolated from the IPX mixture, showed the highest hDPP-IV inhibitory activity. The dissociation constants for hDPP-IV and IC50 values of the peptides were analyzed to understand the reason for the potent inhibitory activity of these tripeptides. The IC50 and Ki values of VPV, VPI, and IPI were found to be 20.2, 22.2, and 46.7 µM and 10.8, 11.3 and 21.4 M−1, respectively. Further, degradation of the peptides by the proteolytic action of hDPP-IV was analyzed to understand the stability of these peptides. Peptides with lower Ki and IC50 values showed relatively slower degradation when incubated with hDPP-IV. These results suggested that a peptide might have higher hDPP-IV inhibitory activity because of its higher affinity and stronger resistance to hDPP-IV, which is caused by the introduction of a hydrophobic amino acid at the C-terminal end of its VP or IP sequence.
... Subsequently, the limb was released, and the horse was observed by the veterinarian during the immediate trotting movement. The horse was trotted in a straight line for at least 20-30 m, in both directions [13]. The results were on a scale of 0 to 3 [14] (0: no reaction/negative; 1: mild reaction; 2: moderate reaction; 3: severe reaction). ...
Simple Summary
This paper reports the efficacy of Ultramicronized Palmitoylethanolamide (PEA-um) supplementation for four show-jumping horses with lameness and joint disease. Joint disease is often associated with inflammatory states and pain that lead to lameness or impairment in athletic performances. PEA-um is a nutraceutical compound that is well-known for its anti-inflammatory and analgesic proprieties, and is widely used in human medicine and small animal veterinary medicine. Although it includes a small number of cases, our study describes for the first time the efficacy of the use of PEA-um in horses. PEA-um was introduced to the normal diet of four horses with non-responsive lameness and significant impairment of athletic performance. After four months of PEA-um supplementation, all horses showed remissions of lameness that led to their reintroduction into showjumping competitions without disease recurrence. Therefore, despite the small number of cases included in this study, the observations suggest that PEA-um may be beneficial in the maintenance of joint disease in athletic horses.
Abstract
Background: Four show jumping horses were evaluated for non-responsive lameness, which caused their withdrawal from show jumping competitions. The clinical evaluation was performed by radiographic examination, flexion tests, diagnostic anesthesia and lameness evaluation using the American Association of Equine Practitioners (AAEP) scale. The diagnoses were a case of navicular syndrome, a complicated case of chronic navicular syndrome and arthrosis of the distal interphalangeal joint of the right anterior limb and two cases of distal intertarsal joint arthritis. Nutraceuticals are often an important management strategy or coadjutant of pharmacological therapies in joint disease. Ultramicronized Palmitoylethanolamide (PEA-um) is an endogenous fatty acid amide that is well-known for its anti-inflammatory and analgesic proprieties widely used in human medicine and small animal veterinary medicine. Although it includes a small number of cases, our study describes for the first time the efficacy of the use of PEA-um in horses. The four horses with non-responsive lameness and significant impairment in athletic performance were daily treated with PEA-um into their normal diet. After four months of PEA-um supplementation, all horses showed remissions of lameness that led to their reintroduction into showjumping competitions without disease recurrence. Therefore, despite the small number of cases included in this study, these observations suggest a good prospective for developing a controlled experiment to test PEA in a larger cohort of horses.
Objective
Osteoarthritis (OA) is the most common joint disorder in humans and dogs. Due to its chronic progressive nature, the predominant clinical signs after a certain point are pain and immobility. The similar pathogenesis allows conclusions to be drawn from canine to human OA. Current treatments are limited and often attempt to treat OA symptoms rather than improve joint structure and function. Collagen hydrolysates as oral supplements are a promising therapeutic option to achieve this advanced therapeutic aim in both species. The effects of oral supplementation were therefore investigated in canine OA patients.
Method
In a systematic, placebo-controlled, double-blind interventional study in 31 dogs with naturally occurring OA, the efficacy of oral supplementation of specific bioactive collagen peptides (BCP) was tested in comparison to the approved combination of the active substances omega-3 fatty acids and vitamin E. The dogs were examined on a horizontal treadmill with 4 integrated piezoelectric force plates at the beginning and end of a twelve-week test period. At both points, the owners completed a specific questionnaire containing the validated Canine Brief Pain Inventory (CBPI) and the dogs were fitted with accelerometers to record total daily activity data.
Results
Only the oral supplementation of BCP resulted in a significant improvement of several kinetic parameters measured using a force-plate fitted treadmill, and the quality of life assessed by CBPI, while accelerometry was unaffected by the intervention.
Conclusion
The results of this three-month BCP supplementation study using objective measurement parameters in dogs with naturally occurring OA demonstrate an efficacy, suggesting the therapeutic use of BCP in canine OA patients and demonstrating the relevance of this collagen hydrolysate formulation for the treatment of OA in human patients as well.
The purpose of this study was to determine anti-inflammatory and/or chondroprotective effects of Equine Omega Complete (EOC) on cartilage explants stimulated with lipopolysaccharide (LPS). Explants were aseptically prepared from the intercarpal joints of 17 market-weight pigs and placed in culture at 37°C for a total of 120 hours. For the final 96 hours, explants were conditioned with a simulated digestion extract of EOC (0, 36 or 180 μL/mL), and for the final 48 hours explants were stimulated with LPS (0 or 15µg/mL). Media was removed and replaced every 24 hours. Samples from the final 48 hours were analyzed for biomarkers of cartilage inflammation [prostaglandin E2 (PGE2) and nitric oxide (NO)] and cartilage structure [glycosaminoglycan (GAG)]. At the end of the culture period cartilage explants were stained for an estimate of cell viability. Stimulation of unconditioned explants with LPS significantly increased media concentrations of PGE2, GAG and NO compared with that from unstimulated explants. LPS stimulation did not significantly affect cell viability. Both concentrations of EOC prevented significant LPS-stimulated cartilage release of GAG without impairing chondrocyte viability. No other effects of treatment were observed. These data provide evidence for a non-cytotoxic, chondroprotective effect of EOC in cartilage. This in vitro experiment supports the use of EOC in protecting against the detrimental effects of inflammation on cartilage structure.
In recent years, the increase in public awareness of sports has greatly promoted the development of the sports food industry. Sports food provides nutrition to meet the metabolic and energy needs of sports people. The nutritional components of sports food can be divided into basic nutrients and functional factors. Basic nutrients refer to the nutrients or metabolites required by the human body. Functional factors are bioactive ingredients that have potential effects in improving functions of the human body, such as protection of articular cartilage and improving muscle quality. Currently, there are various forms of sports foods in the market, including sports drinks, solid sports foods, semi-solid sports foods, and sports nutrition supplements. The sports food industry has seen many opportunities such as the expanding market, manufacturing technology development, and increasing funds investment. However, it also faces many challenges, such as lack of innovation, insufficient in-depth research, risks, and safety issues. This review would provide theoretical guidance for current sports food manufacture to meet the needs of increasing sports people worldwide.
Osteoarthritis is a common and debilitating disease affecting horses across breeds and disciplines. Although the cornerstone of therapy among equine practitioners remains systemic and local anti-inflammatory medications, this approach only addresses the symptoms of osteoarthritis, rather than modifying the progression of the disease itself. There has been great interest in various biologic and cell-based therapies, such as autologous conditioned serum, platelet-rich plasma, and mesenchymal stem cells, as potentially being disease-modifying osteoarthritis drugs. In vitro and experimental results for these novel modalities are promising. However, although the use of these therapies is now widespread, scientific evidence supporting their efficacy in clinical cases is limited to date. Gene therapy for delivery of anti-inflammatory cytokines or growth factors has also been investigated experimentally with good results but has not entered widespread clinical practice. Standardized definitions of disease and large randomized controlled trials, organized across institutions, are needed improve evidence-based recommendations for osteoarthritis treatment. This review provides a brief overview of what is known about the pathophysiology of osteoarthritis and addresses the current literature for medical treatment of osteoarthritis in the horse.
Currently, in the United States, every fifth adult dog or horse suffers from arthritis. The two most common types of arthritis are osteoarthritis (OA) and rheumatoid arthritis (RA). OA occurs with greater frequency than RA. OA is an inflammatory heterogeneous chronic degenerative joint disease (DJD) characterized by chronic and progressive degradation of the articular cartilage, osteophyte formation, thickening and sclerosis of the subchondral bone, bone marrow lesions, hypertrophy of bone at the margin, synovitis, synovial fluid effusion, and fibrosis. Common clinical signs and symptoms associated with OA in dogs and horses include limping, immobility, stiffness of joints, crepitus, periarticular swelling, palpable effusion, and pain upon manipulation of the joint and limb. The pathophysiology of OA is very complex because there are multiple etiologies for this disease, and as a result, treatment is complicated. Pain and inflammation associated with OA are often managed by pharmacological suppression or surgery among a few other modalities. NSAIDs are known to have severe side effects, and surgery is very expensive, so the use of nutraceuticals appears to be a viable alternative for prevention and treatment of OA. This chapter describes various nutraceuticals that have the potential to exert antioxidative, anti-inflammatory, antinociceptive, and chondroprotective effects in osteoarthritis.
In clinical trials over the past decade, the beneficial effect of orally administered collagen peptides in osteoarthritic dogs has been clearly demonstrated [1] [2] [3]. Although a statistically significant improvement in the lameness and vitality of dogs in general has been documented, the mode of action of the collagen peptide treatment is still under discussion. A previous study [3] indicated that the reduction in lameness and increased mobility in dogs after collagen peptide treatment were associated with a statistically significantly lowered plasma content of MMP-3, which is involved in collagen degradation. In addition, the content of the MMP-antagonist TIMP-1 increased slightly after collagen peptide supplementation, suggesting a direct impact on the cartilage metabolism, particularly on the decrease of extracellular matrix degradation. Based on these findings, the impact of specific collagen peptides (PETA-GILE ®) on cartilage metabolism was tested in canine chondrocytes in the current investigation. In addition to the biosynthesis of various matrix molecules (type II collagen, aggrecan and elastin), the RNA profile of inflammatory cy-tokines and degenerative matrix molecules was investigated. The results showed clearly that the supplementation of specific collagen peptides reduced catabolic processes, as indicated by a statistically significant decrease in in-flammatory cytokines and proteases in canine chondrocytes compared with untreated control experiments. In addition, a statistically significantly enhanced biosynthesis of type II collagen, elastin, and aggrecan was observed. Hence, the current data supports the suggested anti-inflammatory effect of specific collagen peptides, but also clearly demonstrates a pronounced stimu-latory impact on matrix molecule synthesis. A combination of both observed effects might help to explain the previously reported clinical improvements after collagen peptide supplementation. Furthermore, the beneficial effect of How to cite this paper: Schunck, M., M. Schunck et al. 255 the specific collagen peptides was also confirmed in case reports on osteoarth-ritic dogs that demonstrated decreased lameness and increased vitality in the affected animals after PETAGILE treatment.
This review presents the pathogenesis and medical treatment of equine osteoarthritis (OA), focusing on firocoxib. Inhibition of prostaglandin E2 remains a fundamental treatment for decreasing clinical symptoms (ie, pain and lameness) associated with OA in horses. Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the production of prostaglandin E2 from the arachidonic acid pathway, continue to be a mainstay for the clinical treatment of OA. Firocoxib is a cyclooxygenase (COX)-2-preferential NSAID that has been shown to be safe and to have a 70% oral bioavailability in the horse. Three clinical reports identified symptom-modifying effects (reduction in pain and/or lameness) in horses with OA administered the once-daily recommended dose (0.1 mg/kg) of oral firocoxib following 7 days of administration. Other reports have suggested that a one-time loading dose (0.3 mg/kg) of firocoxib provides an earlier (1–3 days) onset of action compared to the recommended dose. It is noteworthy that OA disease-modifying effects have been reported in horses for other COX-2-preferential NSAIDs (meloxicam and carprofen), but have not been attributed to firocoxib due to a lack of investigation to date.
Osteoarthritis (OA) is an important cause of pain, disability and economic loss in humans, and is similarly important in the horse. Recent knowledge on post-traumatic OA has suggested opportunities for early intervention, but it is difficult to identify the appropriate time of these interventions. The horse provides two useful mechanisms to answer these questions: 1) extensive experience with clinical OA in horses; and 2) use of a consistently predictable model of OA that can help study early pathobiological events, define targets for therapeutic intervention and then test these putative therapies. This paper summarises the syndromes of clinical OA in horses including pathogenesis, diagnosis and treatment, and details controlled studies of various treatment options using an equine model of clinical OA.
Objective:
To document the caregiver placebo effect in owners and veterinarians of dogs with lameness from osteoarthritis.
Design:
Prospective, randomized, double-blinded, placebo-controlled, multicenter clinical trial.
Animals:
58 dogs with lameness secondary to osteoarthritis.
Procedures:
Dogs enrolled in the placebo arm of an FDA-approved study were evaluated to determine the relationship between subjective (caregiver responses) and objective (force platform gait analysis) patient outcome measures.
Results:
A caregiver placebo effect for owners evaluating their dog's lameness occurred 39.7% of the time. A caregiver placebo effect occurred 44.8% of the time when veterinarians examined dogs for lameness at a walk, 44.8% of the time when veterinarians examined dogs for lameness at a trot, and 43.1% of the time when veterinarians evaluated dogs for signs of pain on palpation of the joint. This effect was significantly enhanced with time. Mean ground reaction forces (GRFs) remained unchanged for dogs during treatment with the placebo. Individually, of 58 dogs, 5 had GRFs that worsened by ≥ 5% over 42 days, 7 had GRFs that improved by ≥ 5% over 42 days, and 46 had GRFs that remained unchanged.
Conclusions and clinical relevance:
A caregiver placebo effect was common in the evaluation of patient response to treatment for osteoarthritis by both pet owners and veterinarians. Force platform gait analysis was an unbiased outcome measure for dogs with lameness from osteoarthritis. A caregiver placebo effect should be considered when interpreting owner and veterinary reports of patient response to treatment.
Obesity is an increasingly important health problem for both man and dog. Osteoarthritis (OA) is a significant cause of pain and disability in both species. A link between obesity and OA has been established in man, though the exact mechanism of the relationship remains to be fully elucidated - current research supports both biomechanical and biochemical theories. There is good evidence (class I*) to support weight loss as an effective treatment for human knee OA. In the dog, the relationship is just beginning to be investigated. The results of one study in dogs (class IV evidence*) suggest that preventing the development of overweightness and obesity reduces the prevalence of hip dysplasia and OA of the hip and other joints. Three other studies (class III and IV evidence*) support weight loss as an effective treatment for OA in affected overweight and obese dogs. Further research could yield greater understanding of the pathophysiology of this relationship, perhaps identifying novel therapeutic targets. Confirmation and better understanding of the positive effect of treating and preventing obesity on symptoms and prevalence of OA is likely to be valuable in the campaign against canine obesity.
Cartilage matrix degradation generates collagen type II fragments. The objective of this study is to explore the possibility that these collagen fragments may be part of an endogenous metabolic feedback. Initially, collagen fragments were extracted from normal or osteoarthritic cartilage, as part of a matrix fragment preparation. Later, collagen fragments were generated by digestion of bovine collagen type II with bacterial collagenase (col2f). These fragments were added to cultures of isolated chondrocytes (bovine and human) and cartilage explants (human). In a dose-dependent manner, col2f caused inhibition of cell attachment to collagen, inhibition of collagen synthesis, and induction of matrix degradation. In addition, when col2f were added to human cartilage explants, an induction of gelatinase activity was detected in the media. These data sets present first evidence that degradation products of collagen may be directly involved in the regulation of cartilage homeostasis.
The extracellular matrix represents a complex alloy of variable members of diverse protein families defining structural integrity and various physiological functions. The most abundant family is the collagens with more than 20 different collagen types identified so far. Collagens are centrally involved in the formation of fibrillar and microfibrillar networks of the extracellular matrix, basement membranes as well as other structures of the extracellular matrix. This review focuses on the distribution and function of various collagen types in different tissues. It introduces their basic structural subunits and points out major steps in the biosynthesis and supramolecular processing of fibrillar collagens as prototypical members of this protein family. A final outlook indicates the importance of different collagen types not only for the understanding of collagen-related diseases, but also as a basis for the therapeutical use of members of this protein family discussed in other chapters of this issue.
Media supplementation with collagen hydrolysate was hypothesized to increase the collagen content in engineered cartilage. By d28, hydrolysate at 0.5 mg/mL increased type II collagen content and 1 mg/mL increased mechanical properties, total collagen content, and type II collagen content over controls. By d42, however, controls possessed the highest GAG content and compressive Young's modulus. Real-time PCR found that 1 mg/mL increased type II collagen gene expression in d0 constructs, but increased MMP expression with no effect on type II collagen on d28. A 10 mg/mL concentration produced the lowest tissue properties, the lowest type II collagen gene expression on d0, and the highest MMP gene expression on d28. These results indicate that the duration of culture modulates the response of chondrocytes to collagen hydrolysate in 3D culture, transforming the response from positive to negative. Therefore, collagen hydrolysate as a media supplement is not a viable long-term method to improve the collagen content of engineered cartilage tissue.
This tutorial discusses important statistical problems arising in clinical trials with multiple clinical objectives based on different clinical variables, evaluation of several doses or regiments of a new treatment, analysis of multiple patient subgroups, etc. Simultaneous assessment of several objectives in a single trial gives rise to multiplicity. If unaddressed, problems of multiplicity can undermine integrity of statistical inferences. The tutorial reviews key concepts in multiple hypothesis testing and introduces main classes of methods for addressing multiplicity in a clinical trial setting. General guidelines for the development of relevant and efficient multiple testing procedures are presented on the basis of application‐specific clinical and statistical information. Case studies with common multiplicity problems are used to motivate and illustrate the statistical methods presented in the tutorial, and software implementation of the multiplicity adjustment methods is discussed. Copyright © 2013 John Wiley & Sons, Ltd.
To evaluate the relationship between limb function and radiographic evidence of stifle osteoarthrosis (OA) in dogs.
The relationship between force platform data and radiographic OA score was evaluated on 2 separate days using regression analysis. Interday variation was also assessed.
Forty-one dogs with visible lameness and radiographic evidence of stifle OA.
Force platform data were collected at a velocity of 1.7 to 2.0 m/s for 5 trials on day 1 and day 8. Radiographs taken on day 1 were scored using a previously reported OA scoring system.
No significant relationship was found between force platform data and OA score. No significant differences were found between any day 1 and day 8 force platform values.
Although radiographic evidence of stifle OA provides evidence of pathology, it does a poor job of representing limb function. In addition, the absence of significant differences between day 1 and day 8 values in this population of dogs supports use of only a single force platform evaluation before measuring a treatment effect.
The presence of OA in the stifle joint does not correlate with clinical function; radiographic outcome should be used cautiously as a predictor of clinical outcome.
To determine whether either of two magnetic resonance imaging approaches - delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC), or T2 mapping - can detect short-term changes in knee hyaline cartilage among individuals taking a formulation of collagen hydrolysate.
Single center, prospective, randomized, placebo-controlled, double-blind, pilot trial of collagen hydrolysate for mild knee osteoarthritis (OA). Participants were allowed to continue the prior analgesic use. The primary outcome was change in dGEMRIC T1 relaxation time in the cartilage regions of interest at the 24-week timepoint. Secondary endpoints included the change in dGEMRIC T1 relaxation time between baseline and 48 weeks, the change in T2 relaxation time at 0, 24 and 48 weeks, the symptom and functional measures obtained at each of the visits, and overall analgesic use.
Among a sample of 30 randomized subjects the dGEMRIC score increased in the medial and lateral tibial regions of interest (median increase of 29 and 41 ms respectively) in participants assigned to collagen hydrolysate but decreased (median decline 37 and 36 ms respectively) in the placebo arm with the changes between the two groups at 24 weeks reaching significance. No other significant changes between the two groups were seen in the other four regions, or in any of the T2 values or in the clinical outcomes.
These preliminary results suggest that the dGEMRIC technique may be able to detect change in proteoglycan content in knee cartilage among individuals taking collagen hydrolysate after 24 weeks.
The functional integrity of articular cartilage is dependent on the maintenance of the extracellular matrix (ECM), a process which is controlled by chondrocytes. The regulation of ECM biosynthesis is complex and a variety of substances have been found to influence chondrocyte metabolism. In the present study we have investigated the effect of degraded collagen on the formation of type II collagen by mature bovine chondrocytes in a cell culture model. The culture medium was supplemented with collagen hydrolysate (CH) and biosynthesis of type II collagen by chondrocytes was compared to control cells treated with native type I and type II collagen and a collagen-free protein hydrolysate. The quantification of type II collagen by means of an ELISA technique was confirmed by immunocytochemical detection as well as by the incorporation of (14)C-proline in the ECM after a 48 h incubation. Chondrocytes in the control group were maintained in the basal medium for 11 days. The presence of extracellular CH led to a dose-dependent increase in type II collagen secretion. However, native collagens as well as a collagen-free hydrolysate of wheat proteins failed to stimulate the production of type II collagen in chondrocytes. These results clearly indicate a stimulatory effect of degraded collagen on the type II collagen biosynthesis of chondrocytes and suggest a possible feedback mechanism for the regulation of collagen turnover in cartilage tissue.
There is a need for an effective treatment for the millions of people in the United States with osteoarthritis (OA), a degenerative joint disease. The demand for treatments, both traditional and non-traditional, will continue to grow as the population ages.
This article reviews the medical literature on the preclinical and clinical research on a unique compound, collagen hydrolysate. Articles were obtained through searches of the PubMed database (www.pubmed.gov) through May 2006 using several pairs of key words (collagen hydrolysate and osteoarthritis; collagen hydrolysate and cartilage; collagen hydrolysate and chondrocytes; collagen hydrolysate and clinical trial) without date limits. In addition, other sources of information, such as abstracts presented at scientific congresses and articles in the German medical literature not available on PubMed, were reviewed and included based on the authors' judgment of their relevance to the topic of the review.
According to published research, orally administered collagen hydrolysate has been shown to be absorbed intestinally and to accumulate in cartilage. Collagen hydrolysate ingestion stimulates a statistically significant increase in synthesis of extracellular matrix macromolecules by chondrocytes (p < 0.05 compared with untreated controls). These findings suggest mechanisms that might help patients affected by joint disorders such as OA. Four open-label and three double-blind studies were identified and reviewed; although many of these studies did not provide key information--such as the statistical significance of the findings--they showed collagen hydrolysate to be safe and to provide improvement in some measures of pain and function in some men and women with OA or other arthritic conditions.
A growing body of evidence provides a rationale for the use of collagen hydrolysate for patients with OA. It is hoped that ongoing and future research will clarify how collagen hydrolysate provides its clinical effects and determine which populations are most appropriate for treatment with this supplement.
Supplementation by collagen hydrolysate in dogs suffering from osteoarthritis
- Hesse K. J. F.
Hesse, K. J. F. (2006). Supplementation by collagen hydrolysate in dogs suffering from osteoarthritis. Kleintiermedizin, 1, 17-22.
Anatomie und physiologie des hyalinen knorpels
- Martinek V.
Martinek, V. (2003). Anatomie und physiologie des hyalinen knorpels.
Zeitschrift für Sportmedizin, 54, 166-170.
Orally administered collagen hydrolysate halts the progression of osteoarthritits in STR/ort mice
- M Schunck
- C H Schulze
- S Oesser
Schunck, M., Schulze, C. H., & Oesser, S. (2007). Orally administered collagen hydrolysate halts the progression of osteoarthritits in STR/ort
mice. Osteoarthritis Cartilage, 15, 94-95.
Diagnostic Techniques in Equine Medicine
- A. R. S. Barr
Pharmakotherapie bei Haus‐ und Nutztiere
- F. R. Ungemach
National economic cost of equine lameness, colic, and equine protozoal myeloencephalitis (EPM) in the United States
- United States Department of Agriculture
Der Einsatz von Kollagenhydrolysat bei klinisch-orthopädischen Hunden und Hunden mit chronischen Erkrankungen des Bewegungsapparates
- N Weide
Weide, N. (2004). Der Einsatz von Kollagenhydrolysat bei klinisch-orthopädischen Hunden und Hunden mit chronischen Erkrankungen des
Bewegungsapparates. Dissertation Thesis, Tierärztliche Hochschule
Hannover, Germany. Retrived from. http://elib.tiho-hannover.de/dissertations/weiden_ws04.pdf.
Opinion on safety of collagen and a processing method for the production of collagen
- Efsa
EFSA (2005). Opinion on safety of collagen and a processing method for the
production of collagen. EFSA Journal, 174, 1-9.
Specific bioactive collagen peptides (PETAGILE ® ) as supplement for horses with osteoarthritis: A two-centred study
- N Weide
- B Dobenecker
- S Reese
- W Jahn
Weide, N. (2004). Der Einsatz von Kollagenhydrolysat bei klinisch-orthopädischen Hunden und Hunden mit chronischen Erkrankungen des
Bewegungsapparates. Dissertation Thesis, Tierärztliche Hochschule
Hannover, Germany. Retrived from. http://elib.tiho-hannover.de/dissertations/weiden_ws04.pdf.
How to cite this article: Dobenecker B, Reese S, Jahn W, et al.
Specific bioactive collagen peptides (PETAGILE ® ) as
supplement for horses with osteoarthritis: A two-centred
study. J Anim Physiol Anim Nutr. 2018;102(Suppl. 1):16-23.
Traditional multiplicity adjustment methods in clinical trials
- A Dmitrienko
- R Agostino