gms | German Medical Science

Objectives: The Liver X Receptors (LXRalpha and LXRbeta)are nuclear receptors with established roles in lipid metabolism and inflammatory signaling. Recent in vitro studies have suggested that LXRs are expressed in articular cartilage tissue and that LXR activation may offer protection against osteoarthritis (OA) by suppression of proteoglycan degradation and chondrocyte hypertrophy. However, a possible protective role of LXR activation on the development of OA has not been investigated in vivo. In this study, we tested the effect of pharmacological LXR activation in a mechanically induced model of knee OA in mice.

Methods: Experimental OA was induced by surgical destabilization of the medial collateral ligament and the medial meniscus (DMM/MLI model) in 11 weeks old male C57BL/6 mice (n=12 per group). After surgery mice were fed with a synthetic LXR agonist T0901317 (Cayman Chemical) at a dosage of 25 mg/kg/day or placebo on a chow diet. 10 weeks after surgery mice were killed and joints were harvested. OA pathology were assessed by histologic analysis with coronal serial sections and Safranin O staining and OA severity was determined by the Osteoarthritis Research Society International (OARSI) scoring system in a blinded fashion by two independent investigators. Histomorphometric analysis was performed as described previously [1]. As a control, livers were analyzed for mRNA expression of LXR target genes by qRT-PCR.

Results and conclusion: There was significant induction of well know LXR target genes (Abca1, Abcg5) mRNA expression in the livers of mice treated with T0901317, indicating effective systemic activation of LXR signaling. OARSI scores of mice treated with T0901317 were significantly reduced compared to placebo treated mice both in medial femoral (1.8 vs.3.9, p=0.01) and medial tibial (1.4 vs.4.8, p=0.001) cartilage. Histomorphometry revealed significantly increased Safranin O staining density in the medial tibial cartilage (57024 vs.42921, p=0.03). As expected for the DMM/MLI model, the lateral compartment showed only moderate OA development in the femoral (0.6 vs.1.1, p=0.2) and tibial (0.5 vs.0.6, p=0.6) cartilage. This study reveals that LXR activation represents an effective means of inhibiting the development and progression of knee OA in vivo. These findings open the perspective of further preclinical testing of pharmacological LXR activation, in particular with intra-articular application.