gms | German Medical Science

Objective: The Liver X Receptors (LXRα and LXRβ) are nuclear receptors that have central roles in regulation of cholesterol and lipid metabolism and inflammatory signaling. Recent studies have suggested that LXRs are expressed in cartilage tissue and possess roles that offer protection against osteoarthritis (OA). Interestingly, the activation of LXR by synthetic agonists have been shown to suppress proteoglycan degradation and suppress chondrocyte hypertrophy. However, a possible protective role of LXR activation on the development of OA have not been investigated in vivo. In this study, we tested the effects of LXR activation in a mechanically induced model of OA in different dietary conditions.

Methods: Experimental OA was induced by surgical transection of the medial collateral ligament and removal of the anterior horn of 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 and on a high fat 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 were determined by scoring using Osteoarthritis Research Society International (OARSI) scoring system by two independent investigators and histomorphometry analysis. Liver of mice were analyzed for mRNA expression of LXR target genes by RT-PCR.

Results: There was significant induction of well know LXR target genes (Abca1, Abcg5) mRNA expression in the livers of mice treated with T0901317 suggesting effective activation of LXR. OARSI scores of mice treated with T0901317 on a chow diet 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. In contrast to mice fed on a chow diet, LXR activation did not protect from OA in mice fed with a HFD both at the medial femoral (3.8 vs. 3.3, p=0.6) and medial tibial (4.8 vs. 4.3, p=0.7) cartilage. Again there were no strong induction of OA in the lateral compartment. Taken together, this study shows that LXR activation protects from the development of OA on normal dietary conditions. However, administration of HFD completely blunted the effects of LXR activation suggesting modulation of cartilage homeostasis by systemic metabolism.

Conclusion: 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.