Molecular network of cartilage homeostasis and osteoarthritis

Abstract

This review article presents the current understanding of the molecular basis of articular cartilaginous homeostasis, and outlines potential areas to focus on within the developing field of therapeutics for cartilage disorders. Articular cartilage, an integral component of joints in extremities and the vertebral column, is essential for locomotion. Disturbance of joint development or cartilage homeostasis causes congenital osteocartilaginous dysplasia or osteoarthritic diseases, respectively. Symptomatic treatments and surgical replacement of joints are effective but can also be problematic in terms of quality of life over time. Recently, new insights into the molecular biological basis of chondrocyte differentiation and cartilage homeostasis have been reported. While joint formation is regulated by several growth factors such as Wnts (wingless-related MMTV integration site) and Gdfs (growth and differentiation factors), the pathology of osteoarthritis is now interpreted as the disruption of balance between anabolic and catabolic signals. Current findings in molecular biology on joint development are reviewed concisely to aid in the understanding of the molecular network that governs articular cartilage development and homeostasis.

Dkk‐1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice

“…In an attempt to elucidate the inhibitory mechanisms of OA cartilage destruction by Dkk-1, we examined expression of Dkk1 under pathogenic conditions, treating primary culture mouse articular chondrocytes with interleukin-1␤ (IL-1␤), a major proinflammatory cytokine involved in OA pathogenesis (1,2). Consistent with the results observed in OA cartilage, IL-1␤ significantly increased Dkk1 expression and decreased Dkk2 expression in chondrocytes ( Figure 6A).…”

“…Biophysical and biochemical factors, including mechanical stress and proinflammatory cytokines, respectively, are responsible for the activation of catabolic pathways and initiation of OA cartilage destruction (1,2). Activation of certain biochemical pathways in chondrocytes-unique resident cells that synthesize cartilage-specific extracellular matrix (ECM) components as well as various catabolic and anabolic factorseventually leads to cartilage destruction.…”

“…Activation of certain biochemical pathways in chondrocytes-unique resident cells that synthesize cartilage-specific extracellular matrix (ECM) components as well as various catabolic and anabolic factorseventually leads to cartilage destruction. Among the articular chondrocyte biochemical pathways important in this context are those leading to the production of matrix metalloproteinases (MMPs) and ADAMTS, which are involved in the degradation of the ECM (1,2). However, the molecular pathogenic mechanisms of OA are not understood in sufficient detail to allow the development of effective therapeutic targets for OA treatment.…”

Switching gears to an arthritis gene expression network by SirT1 cleavage

“…The molecular mechanism underlying cartilage homeostasis is the central issue in arthritis research (1,2). It is well known that inflammatory cytokines, including tumor necrosis factor ␣ (TNF␣) and interleukin-1␤, are up-regulated in arthritic joint tissue and that cell signaling triggered by these effectors disrupts articular cartilage homeostasis.…”

“…It is well known that inflammatory cytokines, including tumor necrosis factor ␣ (TNF␣) and interleukin-1␤, are up-regulated in arthritic joint tissue and that cell signaling triggered by these effectors disrupts articular cartilage homeostasis. This forces a change in the gene expression network from an anabolic to a catabolic phase (1,2).…”