Osteoarthritis: Novel Molecular Mechanisms Increase Our Understanding of the Disease Pathology

Abstract

Although osteoarthritis (OA) is the most common musculoskeletal condition that causes significant health and social problems worldwide, its exact etiology is still unclear. With an aging and increasingly obese population, OA is becoming even more prevalent than in previous decades. Up to 35% of the world's population over 60 years of age suffers from symptomatic (painful, disabling) OA. The disease poses a tremendous economic burden on the health-care system and society for diagnosis, treatment, sick leave, rehabilitation, and early retirement. Most patients also experience sleep disturbances, reduced capability for exercising, lifting, and walking and are less capable of working, and maintaining an independent lifestyle. For patients, the major problem is disability, resulting from joint tissue destruction and pain. So far, there is no therapy available that effectively arrests structural deterioration of cartilage and bone or is able to successfully reverse any of the existing structural defects. Here, we elucidate novel concepts and hypotheses regarding disease progression and pathology, which are relevant for understanding underlying the molecular mechanisms as a prerequisite for future therapeutic approaches. Emphasis is placed on topographical modeling of the disease, the role of proteases and cytokines in OA, and the impact of the peripheral nervous system and its neuropeptides.

Keywords: OA; cartilage; cytokines; inflammation; joint innervation; macrophages; neuropeptides; subchondral bone; synovitis; topographical pattern.

Figure 1

Topographic pattern of osteoarthritis (OA) in sheep and human tibial plateaus. (A) Representative 3-dimensional (3D) microcomputed-tomography (micro-CT) reconstruction and color-coded 3D models of trabecular thickness (Tb.Th) and separation (Tb.Sp) of the subarticular spongiosa of the anterior medial tibial plateau of a normal and an osteoarthritic sheep 6 weeks after OA induction by anterior partial meniscectomy. (B) Structural overview and color-coded 3D micro-CT models of articular cartilage and subchondral bone plate thickness of a representative human tibial plateau.

Figure 2

Proteases and cytokines in the joint. The different cell types present in the joint secrete proteases that degrade the complex cartilage extracellular matrix (ECM). This leads to a release of large protein fragments as well as the generation of small bioactive peptides. These degradation products can stimulate cells to produce more proteases and/or cytokines and chemokines that act either in an autocrine or paracrine manner and enhance the degeneration process in OA. In addition, cytokines and chemokines can influence the polarization of macrophages as well as the differentiation of stem cells. IL, interleukin; TNF, tumor necrosis factor; MMP, matrix metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs.

Figure 3

Sensory neuropeptides modulate bone and cartilage metabolism. (A) Effects of αCGRP (alpha-calcitonin gene-related peptide) and SP (substance P) on bone cell metabolism. Whereas αCGRP exerts mainly anabolic effects, SP signaling has an ambivalent nature. (B) Both substance P and αCGRP decrease proliferation of OA chondrocytes. (C) Stimulation of synovial fibroblasts with SP induces release of inflammatory mediators promoting cartilage degradation. (D) Application of mechanical load increases expression of NK1R (neurokinin 1 receptor) and endogenous synthesis of Substance P. CRLR, calcitonin receptor-like receptor; PGE2, prostaglandin E₂. Adapted from reference [10].