Osteoarthritis is a heterogeneous disorder. The goals of this review are (1) To stimulate use of standardized nomenclature for osteoarthritis (OA) that could serve as building blocks for describing OA and defining OA phenotypes, in short to provide unifying disease concepts for a heterogeneous disorder; and (2) To stimulate establishment of ROAD (Risk of Osteoarthritis Development) and ROAP (Risk of Osteoarthritis Progression) tools analogous to the FRAX™ instrument for predicting risk of fracture in osteoporosis; and (3) To stimulate formulation of tools for identifying disease in its early preradiographic and/or molecular stages -- REDI (Reliable Early Disease Identification). Consensus around more sensitive and specific diagnostic criteria for OA could spur development of disease modifying therapies for this entity that has proved so recalcitrant to date. We fully acknowledge that as we move forward, we expect to develop more sophisticated definitions, terminology and tools.

The extracellular matrix (ECM) plays an important role in cancer progression. It can be divided into the basement membrane (BM) that supports epithelial/endothelial cell behavior and the interstitial matrix (IM) that supports the underlying stromal compartment. The major components of the ECM are the collagens. While breaching of the BM and turnover of e.g. type IV collagen, is a well described part of tumorigenesis, less is known regarding the impact on tumorigenesis from the collagens residing in the stroma. Here we give an introduction and overview to the link between tumorigenesis and stromal collagens, with focus on the fibrillar collagens type I, II, III, V, XI, XXIV and XXVII as well as type VI collagen. Moreover, we discuss the impact of the cells responsible for this altered stromal collagen remodeling, the cancer associated fibroblasts (CAFs), and how these cells are key players in orchestrating the tumor microenvironment composition and tissue microarchitecture, hence also driving tumorigenesis and affecting response to treatment. Lastly, we discuss how specific collagen-derived biomarkers reflecting the turnover of stromal collagens and CAF activity may be used as tools to non-invasively interrogate stromal reactivity in the tumor microenvironment and predict response to treatment.

Bone resorption may generate collagen fragments such as ICTP and CTX, which can be quantified in serum and/or urine by using specific immunoassays, and which are used as clinical markers. However, the relative abundance of ICTP and CTX varies according to the type of bone pathology, suggesting that these two fragments are generated through distinct collagenolytic pathways. In this study, we analyzed the release of ICTP and CTX from bone collagen by the proteinases reported to play a role in the solubilization of bone matrix. Cathepsin K released large amounts of CTX, but did not allow a detectable release of ICTP. Conversely, the matrix metalloproteinases (

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Osteoarthritis (OA) is the biggest unmet medical need among the many musculoskeletal conditions and the most common form of arthritis. It is a major cause of disability and impaired quality of life in the elderly. We review several ambitious but failed attempts to develop joint structure-modifying treatments for OA. Insights gleaned from these attempts suggest that these failures arose from unrealistic hypotheses, sub-optimal selection of patient populations or drug dose, and/or inadequate sensitivity of the trial endpoints. The long list of failures has prompted a paradigm shift in OA drug development with redirection of attention to: (1) consideration of the benefits of localized vs systemic pharmacological agents, as indicated by the increasing number of intra-articularly administered compounds entering clinical development; (2) recognition of OA as a complex disease with multiple phenotypes, that may each require somewhat different approaches for optimizing treatment; and (3) trial enhancements based on guidance regarding biomarkers provided by regulatory agencies, such as the Food and Drug Administration (FDA), that could be harnessed to help turn failures into successes.