University of California, Los Angeles Los Angeles United States
Injured articular cartilage evidences little intrinsic regenerative capacity. When healing does occur, either as a result of a full thickness defect or microfracture surgery designed to mimic this event, mesenchymal cells from the bone marrow BM-MSCs produce disorganized collagen, with a pronounced bias toward collagen I COL I in lieu of collagen II COL II. As a result, the newly-formed fibrocartilage has poor biomechanical properties and often evidences poor integration with the surrounding, native COL II-expressing cartilage, thus priming the tissue for subsequent degeneration. Identification of factors that drive fibrocartilage generation at the site of injury defines a new potential avenue of intervention in the field of cartilage restoration. We defined the lysophosphatidic acid LPA-autotaxin ATX encoded by the ENPP2 gene signaling axis as an important mediator of fibrocartilage formation both in vitro and in vivo. Addition of LPA to cultures of human chondrocytes and BM-MSCs substantially increased expression of COL I at the expense of COL II this outcome could be reversed by small molecule or genetic inhibition of ATX activity. Importantly, drug-based inhibition of ATX activity led to reduced COL I expression and increased the secretion of COL II in a rat model similar to microfracture, thereby improving the quality of neocartilage formed after full-thickness injury.