Exp Mol Med.
2016 Sep;48(9):e257. 10.1038/emm.2016.78.
Osteoactivin inhibition of osteoclastogenesis is mediated through CD44-ERK signaling
- Affiliations
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- 1Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), College of Medicine, Rootstown, OH, USA. fayez.safadi@neomed.edu
- 2School of Biomedical Sciences, Kent State University, Kent, OH, USA.
- 3Department of Pharmaceutical Sciences, Northeast Ohio Medical University (NEOMED), College of Pharmacy, Rootstown, OH, USA.
- 4Department of Biological Sciences, Kent State University, Kent, OH, USA.
- 5Department of Biology, King Abdulaziz University, Jeddah, KSA.
- 6Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA.
- 7Department of Orthopedics, Summa Health Systems, Akron, OH, USA.
- KMID: 2361544
- DOI: http://doi.org/10.1038/emm.2016.78
Abstract
- Osteoactivin is a heavily glycosylated protein shown to have a role in bone remodeling. Previous studies from our lab have shown that mutation in Osteoactivin enhances osteoclast differentiation but inhibits their function. To date, a classical receptor and a signaling pathway for Osteoactivin-mediated osteoclast inhibition has not yet been characterized. In this study, we examined the role of Osteoactivin treatment on osteoclastogenesis using bone marrow-derived osteoclast progenitor cells and identify a signaling pathway relating to Osteoactivin function. We reveal that recombinant Osteoactivin treatment inhibited osteoclast differentiation in a dose-dependent manner shown by qPCR, TRAP staining, activity and count. Using several approaches, we show that Osteoactivin binds CD44 in osteoclasts. Furthermore, recombinant Osteoactivin treatment inhibited ERK phosphorylation in a CD44-dependent manner. Finally, we examined the role of Osteoactivin on receptor activator of nuclear factor-κ B ligand (RANKL)-induced osteolysis in vivo. Our data indicate that recombinant Osteoactivin inhibits RANKL-induced osteolysis in vivo and this effect is CD44-dependent. Overall, our data indicate that Osteoactivin is a negative regulator of osteoclastogenesis in vitro and in vivo and that this process is regulated through CD44 and ERK activation.
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