ECTS Abstracts (2015) 1 P193

Homer2/Homer3 Modulate RANKL-Induced NFATc1 Signalling in Osteoclastogenesis

Ga-Yeon Son, Yu-Mi Yang & Dong Min Shin

Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea.

Ca2+ signalling and NFATc1 activation are essential for RANKL-induced osteoclastogenesis through the induction of Ca2+ oscillation, calcineurin activation, and translocation of NFATc1 into the nucleus. Homer proteins are scaffold proteins and have been proposed to modulate the multiple Ca2+ signalling channels and proteins, including inositol 1,4,5-triphosphate receptors, ryanodine receptors, transient receptor potential channels, and NFAT family of transcription factors in skeletal muscle cells and T cell. However, the role of Homer proteins in Ca2+ signalling during osteoclast differentiation is not well understood. In the present work, we investigated the role of Homer proteins (Homer2 and Homer3) on RANKL-induced Ca2+ signalling in osteoclasts using Homer2/Homer3 (Homer2/3) double-knockout (DKO) mice. Deletion of Homer2/3 markedly decreased the bone density of the tibias. In contrast, Homer2/3 deletion did not affect osteoblast formation and RANKL-induced Ca2+ oscillation. Forty-eight hours after RANKL treatment, there was a higher level of NFATc1 protein expression and significantly increased translocation of NFATc1 into the nucleus during osteoclastogenesis in the Homer2/3 DKO bone marrow-derived monocytes/macrophages (BMMs). Notably, the interaction of Homer proteins with NFATc1 inhibited its interaction by RANKL treatment, but restored by cyclosporine A treatment to inhibit the binding between NFATc1 and calcineurin in wild-type osteoclasts. In addition, RANKL treatment of Homer2/3 DKO BMMs significantly induced formation of multinucleated cells. These results suggest that Homer2/3 interact with NFATc1 and modulate the NFATc1 pathway in RANKL-induced osteoclastogenesis.

Disclosure: The authors declared no competing interests. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2012R1A2A1A01003487) and (MOE) (2012R1A1A2007673).

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