Liver X Receptor activation delays chondrocyte hypertrophy during endochondral bone growth
Osteoarthritis and Cartilage
URL with Digital Object Identifier
Objective: Activation of the Liver X Receptor (LXR) has recently been identified as a therapeutic strategy for osteoarthritis (OA). Human OA articular cartilage explants show decreased LXR expression, and LXRβ-null mice display OA-like symptoms. LXR agonist administration to OA articular cartilage explants suppresses proteoglycan degradation and restores LXR-activated transcription. We aimed to investigate the effect of LXR activation on chondrocyte differentiation to elucidate the molecular mechanisms behind its protection against OA. Method: The specific LXR agonist, GW3965, was used to examine the effect of LXR activation on chondrocyte differentiation. Tibia organ cultures were used to examine the effect of LXR activation on bone growth and growth plate morphology, followed by immunohistochemical analysis. In ATDC5 and micromass cultures, chondrocyte differentiation was examined through cellular staining and proliferation assays. Various chondrogenic markers were analyzed by real-time reverse-transcription polymerase chain reaction (qRT-PCR) in micromass RNA. Results: Chondrocyte hypertrophy was suppressed by GW3965 treatment, as shown by decreased hypertrophic zone length in the tibial growth plate, decreased alkaline phosphatase staining in ATDC5 and micromass cultures, and down regulation of Col10a1, Mmp13 and Runx2 expression. Increased proliferation in treated ATDC5 cells and up-regulation of Col2a1 expression in treated micromass cultures suggest hypertrophy is suppressed secondary to prolonged proliferation. Decreased p57 levels in treated growth plates suggest this to be due to cell-cycle exit delay. Conclusion: Our findings regarding LXR's role in cartilage development provide insight into how LXR activation prevents cartilage breakdown, further solidifying its potential as a therapeutic target of OA. © 2014 Osteoarthritis Research Society International.