Conjugated linoleic acid inhibits osteoclast differentiation of RAW264.7 cells by modulating RANKL signaling

Md Mizanur Rahman, Arunabh Bhattacharya, and Gabriel Fernandes

Medicine, UTHSCSA, San Antonio, TX 78229-3900

Corresponding Author: fernandes{at}uthscsa.edu

Bone destruction is a pathological hallmark of several chronic inflammatory diseases, including rheumatoid arthritis, periodontitis, and osteoporosis. Inflammation-induced bone loss of this sort results from elevated numbers of bone-resorbing osteoclasts. Numerous studies have indicated that conjugated linoleic acid (CLA) positively influences on calcium and bone metabolism. Gene deletion studies have shown that receptor activator of NF-kappaB ligand (RANKL) is one of the critical mediators of osteoclastogenesis. In this report, we examined the ability of CLA to suppress RANKL signaling and osteoclastogenesis in RAW 264.7 cells, a murine monocytic cell line. Treatment of these cells with RANKL activated NF-kappaB, and preexposure of the cells to CLA significantly suppressed RANKL-induced NF-kappaB activation including phosphorylation of IkappaBalpha, degradation of IkappaBalpha and nuclear translocation of p65. RANKL induced osteoclastogenesis in these monocytic cells, and CLA inhibited RANKL-induced TNF-alpha production, and osteoclast differentiation including osteoclast-specific genes like tartrate resistant acid phosphatase (TRAP), cathepsin K, calcitonin receptor (CTR), matrix metalloproteinase (MMP)-9 expression and osteoclasts-specific transcription factors like c-Fos, nuclear factor of activated T-cells (NFATc1) expression, and bone resorptive pit formation. CLA also inhibited RANKL-induced activation of mitogen-activated protein kinase (MAPK), p38 but had little effect on c-Jun N-terminal kinase (JNK) activation. Collectively, these data demonstrate for the first time that CLA inhibits osteoclastogenesis by modulating RANKL signaling. Thus, CLA may have important therapeutic implications for the treatment of bone diseases associated with enhanced bone resorption by excessive osteoclastogenesis.

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