Biomarkers for osteoarthritis: Current position and steps towards further validation
Best practice & research. Clinical rheumatology (Impact Factor: 2.6). 02/2014; 28(1):61-71. DOI: 10.1016/j.berh.2014.01.007
Historically disease knowledge development and treatment innovation in osteoarthritis (OA) has been considered to be slow. One of the many reasons purported as responsible for this slow pace has been the alleged lack of valid and responsive biomarkers to ascertain efficacy, which itself has been dependent upon the slow evolution of the understanding of the complex nature of joint tissue biology. This narrative review outlines the rationale for why we need OA biomarkers with regard to biomarker validation and qualification. The main biomarkers in current development for OA are biochemical and imaging markers. We describe an approach to biomarker validation and qualification for OA clinical trials that has recently commenced with the Foundation of NIH OA Biomarkers Consortium study cosponsored by the Osteoarthritis Research Society International (OARSI). With this approach we endeavor to identify, develop, and qualify biological markers (biomarkers) to support new drug development, preventive medicine, and medical diagnostics for osteoarthritis.
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ABSTRACT: Objective: To assess the association between pain mechanisms (sensitization) and biochemical markers for cartilage, bone, and inflammation in patients with knee pain. Methods: The study group comprised 281 patients with different degrees of knee pain intensity and radiographic findings (using the Kellgren/Lawrence [K/L] scale). The following structurally related serologic biomarkers were measured in serum: high-sensitivity C-reactive protein (hsCRP), matrix metalloproteinase (MMP)-mediated breakdown of CRP (CRPM), MMP-mediated degradation of type I collagen (C1M), C2M, and C3M. Pressure-pain thresholds (PPT) (peripheral and spreading sensitization), temporal summation of pain, and conditioning pain modulation (CPM) (with the latter 2 biomarkers representing generalized sensitization) were assessed. For each pain parameter, the patients were categorized as most sensitized or least sensitized. Results: Correlations were observed between the pain biomarkers PPT, temporal summation, and CPM and maximal pain intensity during the last 24 hours. Significant associations between most of the serologic biomarkers were observed. A high CRPM level was associated with centralized sensitization (temporal summation and CPM). None of the serologic markers correlated with the intensity or duration of knee pain, and only hsCRP correlated with the K/L grade. The most-sensitized group contained more women than men, and the least-sensitized group contained more men than women. Conclusion: A platform of mechanistic pain biomarkers in combination with structure-related serologic biomarkers provides new possibilities for understanding how osteoarthritis-related structural features may be associated with pain and pain sensitization. This study showed significant correlations between central pain sensitization and CRPM as a possible measure for chronic inflammation. Future pain association studies should include biomarkers representing the local joint environment more specifically.
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ABSTRACT: Objectives: To explore the involvement of protease activated receptor (PAR)-1 and PAR-2 in osteoarthritis (OA) joint pathology and the cells/tissues primarily affected by their ablation.Methods: Destabilisation of the medial meniscus (DMM)-induced OA in wild-type (WT), PAR-1+/+, PAR-1-/- and PAR-2-/- mice was compared by histologic scoring (cartilage aggrecan loss and erosion, subchondral-bone sclerosis, osteophytes, synovitis) at 1, 4 and 8 weeks. The effects of PAR ablation on cartilage degradation and chondrocyte metalloproteinase expression/activity were studied in femoral head cultures ± IL-1α. At 1 week-post DMM, synovial cytokine and metalloproteinase gene expression were measured by RT-PCR, and populations of inflammatory cells quantified by flow cytometry.Results: PAR-2-/- but not PAR-1-/- significantly delayed cartilage damage and inhibited subchondral bone sclerosis following DMM. There was no inhibitory effect of PAR-1 or PAR-2 ablation on IL-1α-induced cartilage degradation or chondrocyte metalloproteinase gene expression or activation. A low but significant level of synovitis persisted in DMM compared with sham surgery, but no differences were seen 4 or 8 weeks post-DMM between genotypes. One week after DMM, increased synovial expression of pro-inflammatory cytokines and metalloproteinases, along with increased CD4-T cells, inflammatory monocytes and activated macrophages were seen in all genotypes. However, there was a significant reduction in activated macrophages in PAR-2-/-compared to PAR-1-/- and WT.Conclusion: Deletion of PAR-2 but not PAR-1 significantly decreases DMM-induced cartilage damage. The chondroprotection in PAR-2-/- mice appears to occur indirectly through modulation of extra-cartilaginous events such as subchondral bone remodelling and synovial macrophage activation rather than altering chondrocyte catabolic responses. © 2014 American College of Rheumatology.
Article: Biomarkers of PTA[Show abstract] [Hide abstract]
ABSTRACT: Prognostic biomarkers may indicate the likelihood of disease development and speed of progression or may serve as predictive indicators of responsiveness to treatment. Joint injuries, particularly severe injuries, may result in post-traumatic osteoarthritis (PTOA), and pre- and post-injury prognostic biomarkers are needed to enhance primary and secondary prevention approaches for PTOA. Several macromolecules from joint structures found in serum, urine, and synovial fluid are promising biochemical markers for monitoring joint metabolism and health before and after joint injury. The use of metabolic profiling (analysis of small molecules) as a predictive tool for osteoarthritis (OA) has increased in the past decade. Although there is some question as to whether PTOA and idiopathic OA are comparable conditions, there is some evidence to suggest that components of their pathogenesis are similar. Potentially, biomarkers important to the high-risk PTOA profile translate to idiopathic OA. Further work is needed to confirm the utility of macromolecules and metabolites as biomarkers for PTOA, particularly focusing on those strongly correlated to clinical efficacy measures important to the patient (e.g., symptoms, physical function, and quality of life) and the causal pathway of PTOA.
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