The p75 neurotrophin receptor regulates MC3T3-E1 osteoblastic differentiation.
While the role of p75(NTR) signaling in the regulation of nerve-related cell growth and survival has been well documented, its actions in osteoblasts are poorly understood. In this study, we examined the effects of p75(NTR) on osteoblast proliferation and differentiation using the MC3T3-E1 pre-osteoblast cell line. Proliferation and osteogenic differentiation were significantly enhanced in p75(NTR)-overexpressing MC3T3-E1 cells (p75GFP-E1). In addition, expression of osteoblast-specific osteocalcin (OCN), bone sialoprotein (BSP), and osterix mRNA, ALP activity, and mineralization capacity were dramatically enhanced in p75GFP-E1 cells, compared to wild MC3T3-E1 cells (GFP-E1). To determine the binding partner of p75(NTR) in p75GFP-E1 cells during osteogenic differentiation, we examined the expression of trkA, trkB, and trkC that are known binding partners of p75(NTR), as well as NgR. Pharmacological inhibition of trk tyrosine kinase with the K252a inhibitor resulted in marked reduction in the level of ALPase under osteogenic conditions. The deletion of the GDI binding domain in the p75(NTR)-GFP construct had no effect on mineralization. Taken together, our studies demonstrated that p75(NTR) signaling through the trk tyrosine kinase pathway affects osteoblast functions by targeting osteoblast proliferation and differentiation.
Department of Anatomy, Nihon University School of Dentistry, Tokyo, Japan. mikami-t@dent.nihon-ua.c.jp
Yoshikazu
Y
Mikami
Shinnosuke
S
Suzuki
Yumiko
Y
Ishii
Nobukazu
N
Watanabe
Tomihisa
T
Takahashi
Keitaro
K
Isokawa
Masaki J
MJ
Honda
D000818:Animals; D002113:Calcification, Physiologic; D002227:Carbazoles; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D026121:Indole Alkaloids; D058574:Integrin-Binding Sialoprotein / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000096:biosynthesis; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D002227:Carbazoles; D026121:Indole Alkaloids; D058574:Integrin-Binding Sialoprotein; D012333:RNA, Messenger; D017475:Receptors, Nerve Growth Factor; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; C517634:Ngfr protein, mouse; D014157:Transcription Factors; D015675:Osteocalcin; C049985:staurosporine aglycone; D020812:Receptor, trkC; D011493:Protein Kinase C