LPCAT3-ABCA1 axis regulates the dose-sparing effects of steroid drugs in osteoarthritis in mice

Osteoarthritis (OA) is characterized as a progressive synovial cartilage degenerative disorder with no curative drugs. Intra-articular (IA) injection of steroids has been approved and used for the management of pain and further loss of cartilage in patients. However, meta-analysis suggests that IA-usage of high-dose steroids was associated with osteonecrosis, subchondral insufficiency fracture, and rapid joint destruction with bone loss. Upregulation of lysophosphatidylcholine acyltransferase 3 (LPCAT3) has been demonstrated in OA and was correlated with the severity of the disease. The current study unveils that LPCAT3 plays a critical role in the cellular efflux of a steroidal drug (methylprednisolone; MPD) through post-translational regulation and stabilization of a steroid efflux protein, ATP-Binding Cassette Subfamily A Member 1 (ABCA1). Gene silencing of LPCAT3 downregulates ABCA1 protein through ubiquitination and degradation in the chondrocytes. This loss of ABCA1 favors increased cellular retention of MPD, thereby reducing the minimal effective dosage of MPD and promoting the anti-inflammatory benefits of MPD. Conversely, the Liver X Receptor (LXR) agonist (T0901317) completely reversed the LPCAT3-induced alterations of ABCA1 and steroid retention in the cells. Consistent with the in vitro studies, IA administration of LPCAT3 siRNA liposomes downregulates ABCA1 in the synovium and potentiates the therapeutic benefits of MPD at much smaller doses in the Destabilization of the Medial Meniscus (DMM) surgery-induced OA in mice. This study reveals a previously unrecognized role of ABCA1 in the MPD steroidal drug-efflux. Thus, targeting the LPCAT3-ABCA1 axis causes a drug sparing effect on steroids by enhancing their intracellular retention and improving their therapeutic efficiency in OA.