Osteoarthritis Pathway

Osteoarthritis is the progressive degradation of joints such as the knee, with an endpoint of pain and complete loss of function. Joints are characterized by cartilage which forms the durable lubricating surface between two bones, and has limited metabolic, replicative, and repair capacity. Cartilage occupies an intermediate developmental state, as most bone develops from cartilage, but some cartilage is specifically arrested in this process (ossification) to provide the stable adult tissue. Chondrocytes are the main or only cell type within cartilage, secreting and enveloping themselves in a complex extracellular matrix composed of, among others, collagen (mostly type II), aggrecan, hyaluronan, lubricin, and fibronectin.Major risk factors for osteoarthritis are age, injury, obesity, inflammation, and lack of regular exercise. With age, the repair capability of cartilage declines dramatically, while regular moderate loading via exercise releases beneficial factors such as TGFβ. Chondrocytes, in order to effect any repair, need to secrete a variety of degradative enzymes to escape their matrix capsule, thus there is a fine balance between repair and degradation. While osteoarthritis involves other tissues of the joint, such as synovial fibroblasts and immune cells, most work has focused on chondrocytes, which are found to undergo complex changes, including extensive degradative enzyme secretion, hypertrophy, and apoptosis, along with the formation of osteophytes from other mesenchymal stem cells. This all closely resembles the normal developmental transition from cartilage to bone, which has thus served as a major focus and model of research into the molecular mechanisms of osteoarthritis.Chondrocytes have two major axes of transcriptional regulation, focused on SOX9 as a protective, stabilizing factor, and RUNX2 as a pro-development, pro-degradation, pro-osteoarthritis factor. These axes are mutually inhibitory, and respond to many signals and pathways, principally the SMAD2/3 pathway for SOX9, downstream from TGFβ stimulation, and the SMAD1/5/8 and NFκB pathways, induced by BMP growth factors, IL1β, matrix fragments and other danger signals (DAMPS), and by inflammation in general, for RUNX2.The RUNX2 and related pro-osteoarthritis factors induce a large variety of effector proteins, such as metalloproteases (MMPs and ADAMTSs), further inflammatory cytokines, and bone-promoting factors such as osteocalcin and osteopontin. Thus the pro-osteoarthritis pathways generate autocrine self-activating loops which can, unless countered by other events, and degrade cartilage to the point of symptomatic decline and destruction.