Inhibition of Autotaxin Attenuates High-Fat Diet-Induced or Surgically-Induced Acceleration of Osteoarthritis

Purpose: Osteoarthritis (OA) is the most common form of arthritis worldwide. Aetiologies of this disease are poorly defined; however, epidemiological studies suggest that obese individuals have an increased incidence of OA. Presently it is believed that Obesity increases the risk of developing Osteoarthritis (OA). Recent evidence suggests that after weight loss, a metabolic adaptation persists long after alteration of body composition. In high fat diet (HFD)-fed mice, which show acceleration of OA, we identified a signature rich in lysophosphatidyl cholines (lysoPC) analogues that was sustained up to at least 9-months of age. We also identified that changes in leptin in the HFD-fed mice knee joints are sustained and that leptin increases the expression of MMP13 by an autotaxin (ATX)-dependent mechanism. ATX is an enzyme responsible for the conversion of lysoPC to the inflammatory mediator lysophosphatidic acid (LPA). Presently, we sought to identify if local pharmacological inhibition of ATX can attenuate diet or surgically-induced OA pathogenesis in vivo and the contribution of LPA to the catabolic phenotype of chondrocytes in vitro. Methods: Nine week-old mice were fed HFD for 18 weeks or 9 week-old mice were subjected to surgically-induced OA. ATX antagonist was injected intra-articularly in the knee joints and subsequent knee joint pathology was evaluated. Primary human chondrocytes were treated with various agents, including ATX antagonist, and the release/expression of selected metabolites or enzymes was determined. Results: Local injection of ATX antagonist reduced the degree of OA pathogenesis in surgically induced OA models compared to saline injected controls. In vitro, LPA increased the expression of MMP13, suggesting that ATX contributes to LPA production in chondrocytes, consistent with our previous observations that ATX antagonist blocks MMP13 expression. Conclusions: Inhibition of ATX attenuates surgically-induced OA, likely by modulating the production of MMP13 through blocking of the conversion of local lysoPCs to LPA. We continue to examine pre-clinical efficacy of ATX inhibition in HFD-fed mice. Our data, to date, suggests pre-clinical efficacy of ATX to limit OA progression.