Dual function of Bmpr1a signaling in restricting preosteoblast proliferation and stimulating osteoblast activity in the mouse

Abstract

Exogenous bone morphogenetic proteins (Bmp) are well known to induce ectopic bone formation, but the physiological effect of Bmp signaling on normal bone is not completely understood. By deleting the receptor Bmpr1a in osteoblast lineage cells with Dmp1-Cre, we observed a dramatic increase in trabecular bone mass in postnatal mice, which was due to a marked increase in osteoblast number that was likely to be driven by hyperproliferation of Sp7 + preosteoblasts. Similarly, inducible deletion of Bmpr1a in Sp7 + cells specifically in postnatal mice increased trabecular bone mass. However, deletion of Smad4 by the same approaches had only a minor effect, indicating that Bmpr1a signaling suppresses trabecular bone formation through effectors beyond Smad4. Besides increasing osteoblast number in the trabecular bone, deletion of Bmpr1a by Dmp1-Cre also notably reduced osteoblast activity, resulting in attenuation of periosteal bone growth. The impairment in osteoblast activity correlated with reduced mTORC1 signaling in vivo, whereas inhibition of mTORC1 activity abolished the induction of protein anabolism genes by BMP2 treatment in vitro. Thus, physiological Bmpr1a signaling in bone exerts a dual function in both restricting preosteoblast proliferation and promoting osteoblast activity.

Sex-Dependent, Osteoblast Stage-Specific Effects of Progesterone Receptor on Bone Acquisition

“…However, hormone deficiency during the rapid growing period induced a similar rate of trabecular bone loss in the Prx1; PRcKO mice in both sexes, suggesting that the ligand‐dependent role of PR signaling in the MSCs is directed at skeleton accrual. Additionally, Dmp1‐Cre targeted a broader cell population than osteocytes, and it is activated in early osteoblast lineage cells, in bone marrow cells and in tissue not related to bone . Selective deletion of PR in Dmp1+ cells resulted in a modest higher trabecular bone mass and bone strength.…”

“…These results confirm other reports that Dmp1 marked a broader cell population than just the "osteocytes." (25,36,37) Distal femur trabecular BV/TV and middle femur cortical bone volume differed between the sexes in both the WT and mutant mice but were not different between the genotypes at 2 and 4 months of age (Fig. 6B).…”

Bmp Induces Osteoblast Differentiation through both Smad4 and mTORC1 Signaling

“…In particular, Wnt-induced mTORC1 signaling leads to intracellular glutamine deficiency that activates the integrated stress response (ISR), resulting in the upregulation of protein anabolism genes (23). Although mTORC1 is also activated by Bmp, it is not known whether Bmp employs the same amino acid-based ISR mechanism to enhance the protein synthesis capacity during osteoblast differentiation (27).…”

The Role of the Osteocyte in Bone and Nonbone Disease

“…Regulate bone formation through Bmpr1a signaling 146 , Notch activation 147 , and ERαsignaling 148,149 …”