The Extracellular Matrix of Articular Cartilage Controls the Bioavailability of Pericellular Matrix-Bound Growth Factors to Drive Tissue Homeostasis and Repair.

The extracellular matrix (ECM) has long been regarded as a packing material; supporting cells within the tissue and providing tensile strength and protection from mechanical stress. There is little surprise when one considers the dynamic nature of many of the individual proteins that contribute to the ECM, that we are beginning to appreciate a more nuanced role for the ECM in tissue homeostasis and disease. Articular cartilage is adapted to be able to perceive and respond to mechanical load. Indeed, physiological loads are essential to maintain cartilage thickness in a healthy joint and excessive mechanical stress is associated with the breakdown of the matrix that is seen in osteoarthritis (OA). Although the trigger by which increased mechanical stress drives catabolic pathways remains unknown, one mechanism by which cartilage responds to increased compressive load is by the release of growth factors that are sequestered in the pericellular matrix. These are heparan sulfate-bound growth factors that appear to be largely chondroprotective and displaced by an aggrecan-dependent sodium flux. Emerging evidence suggests that the released growth factors act in a coordinated fashion to drive cartilage repair. Thus, we are beginning to appreciate that the ECM is the key mechano-sensor and mechano-effector in cartilage, responsible for directing subsequent cellular events of relevance to joint health and disease.

Targeting Cartilage Degradation in Osteoarthritis.

Osteoarthritis is a common, degenerative joint disease with significant socio-economic impact worldwide. There are currently no disease-modifying drugs available to treat the disease, making this an important area of pharmaceutical research. In this review, we assessed approaches being explored to directly inhibit metalloproteinase-mediated cartilage degradation and to counteract cartilage damage by promoting growth factor-driven repair. Metalloproteinase-blocking antibodies are discussed, along with recent clinical trials on FGF18 and Wnt pathway inhibitors. We also considered dendrimer-based approaches being developed to deliver and retain such therapeutics in the joint environment. These may reduce systemic side effects while improving local half-life and concentration. Development of such targeted anabolic therapies would be of great benefit in the osteoarthritis field.