Mutation in Osteoactivin Promotes RANKL-Mediated Osteoclast Differentiation and Survival, but Inhibits Osteoclast Function [Signal Transduction]

April 2nd, 2015 by Abdelmagid, S. M., Sondag, G. R., Moussa, F. M., Belcher, J. Y., Yu, B., Stinnett, H., Novak, K., Mbimba, T., Khol, M., Hankenson, K. D., Malcuit, C., Safadi, F. F.

We previously reported on the importance of osteoactivin (OA/Gpnmb) in osteogenesis. In this study, we examined the role of OA in osteoclastogenesis, using mice with a nonsense mutation in Gpnmb gene (D2J) and wild-type controls (D2J/Gpnmb+). In these D2J mice, micro-CT and histomorphometric analyses revealed increased cortical thickness, while total porosity and eroded surface were significantly reduced in D2J mice compared to wild-type controls, and these results were corroborated by lower serum levels of CTX-1. Contrary to these observations, and counterintuitively, temporal gene expression analyses supported up-regulated osteoclastogenesis in D2J mice, and increased osteoclast differentiation rates ex vivo, marked by increased number and size. The finding that MAPK was activated in early differentiating and mature D2J osteoclasts, and survival of D2J osteoclasts was enhanced and mediated by activation of the AKT-GSK3β pathway supports this observation. Furthermore, this was abrogated by the addition of recombinant OA to cultures, which restored osteoclastogenesis to wild-type levels. Moreover, mix and match co-cultures demonstrated an induction of osteoclastogenesis in D2J osteoblasts co-cultured with osteoclasts of D2J or wild-type. Lastly, in functional Osteo-Assays we show that bone resorption activity of D2J osteoclasts is dramatically reduced, and these osteoclasts present abnormal ruffled border over bone surface. Collectively, these data support a model whereby OA/Gpnmb acts as a negative regulator of osteoclast differentiation and survival but not function by inhibiting the ERK/AKT signaling pathways.
  • Posted in Journal of Biological Chemistry, Publications
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