title: Osteoactivin inhibition of osteoclastogenesis is mediated through CD44-ERK signaling.
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.
authors: Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), College of Medicine, Rootstown, OH, USA.|School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors: Gregory R
authors: GR
authors: Sondag
authors: Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), College of Medicine, Rootstown, OH, USA.|School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors: Thomas S
authors: TS
authors: Mbimba
authors: Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), College of Medicine, Rootstown, OH, USA.|School of Biomedical Sciences, Kent State University, Kent, OH, USA.
authors: Fouad M
authors: FM
authors: Moussa
authors: Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), College of Medicine, Rootstown, OH, USA.|Department of Pharmaceutical Sciences, Northeast Ohio Medical University (NEOMED), College of Pharmacy, Rootstown, OH, USA.
authors: Kimberly
authors: K
authors: Novak
authors: Department of Biological Sciences, Kent State University, Kent, OH, USA.
authors: Bing
authors: B
authors: Yu
authors: Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), College of Medicine, Rootstown, OH, USA.|School of Biomedical Sciences, Kent State University, Kent, OH, USA.|Department of Biology, King Abdulaziz University, Jeddah, KSA.
authors: Fatima A
authors: FA
authors: Jaber
authors: Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), College of Medicine, Rootstown, OH, USA.
authors: Samir M
authors: SM
authors: Abdelmagid
authors: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA.
authors: Werner J
authors: WJ
authors: Geldenhuys
authors: Department of Anatomy and Neurobiology, Northeast Ohio Medical University (NEOMED), College of Medicine, Rootstown, OH, USA.|School of Biomedical Sciences, Kent State University, Kent, OH, USA.|Department of Pharmaceutical Sciences, Northeast Ohio Medical University (NEOMED), College of Pharmacy, Rootstown, OH, USA.|Department of Orthopedics, Summa Health Systems, Akron, OH, USA.
authors: Fayez F
authors: FF
authors: Safadi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005136:Eye Proteins / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C476399:Cd44 protein, mouse; D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D018960:Hyaluronan Receptors; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D011994:Recombinant Proteins; C505689:Tnfsf11 protein, mouse