| First Author | Fulzele K | Year | 2018 |
| Journal | Bone | Volume | 117 |
| Pages | 138-148 | PubMed ID | 30266511 |
| Mgi Jnum | J:267789 | Mgi Id | MGI:6267915 |
| Doi | 10.1016/j.bone.2018.09.021 | Citation | Fulzele K, et al. (2018) Loss of Gsalpha in osteocytes leads to osteopenia due to sclerostin induced suppression of osteoblast activity. Bone 117:138-148 |
| abstractText | The stimulatory subunit of G-protein, Gsalpha, acts as a secondary messenger of G-protein coupled receptors (GPCRs) that primarily activates cAMP-induced signaling. GPCRs, such as the parathyroid hormone receptor (PTHR), are critical regulators of bone formation as shown by number of genetic manipulation studies targeting early osteoblast lineage cells. In this study, we have examined the role of Gsalpha in osteocytes, the terminally differentiated and most abundant cells of the osteoblast lineage. Mice lacking the stimulatory subunit of G-proteins (Gsalpha) in osteocytes (DMP1-GsalphaKO) have significant decrease of both trabecular and cortical bone, as assessed by muCT. Histomorphometric analysis showed that the osteopenia was mostly driven by more than 90% decrease in osteoblast numbers and activity whereas osteoclasts were only slightly decreased. The decrease in osteoblast number was associated with a striking lack of endocortical osteoblasts. We have previously shown that loss of the stimulatory subunit of G-proteins (Gsalpha) in osteocytes in vitro or in vivo induces high expression of sclerostin. To determine if the increased sclerostin levels contributed to the decreased endosteal bone lining cells and osteopenia, we treated wild-type mice with recombinant sclerostin and the DMP1-GsalphaKO mice with anti-sclerostin antibody. Treatment of wild-type mice with 100mug/kg sclerostin for 3-weeks significantly reduced the numbers of bone lining cells and led to osteopenia. Next, the DMP1-GsalphaKO and control littermates were treated with the anti-sclerostin antibody (25mg/kg, 2 times per week) for 4-weeks. Upon the antibody treatment, the endocortical osteoblasts reappeared in the DMP1-GsalphaKO mice to a comparable level to that of the vehicle treated control littermates. In control mice, E11/gp38 positive osteocytes were observed in parallel with the endocortical osteoblasts with higher dendrite density towards the endocortical osteoblasts. In DMP1-GsalphaKO mice, E11/gp38 positive osteocytes were lacking dendrites and were randomly scattered throughout the bone matrix. After treatment with anti-sclerostin antibody, DMP1-GsalphaKO mice showed increased E11/gp38 positive osteocytes near the endosteal bone surface and endosteal osteoblasts. The anti-sclerostin antibody treatment proportionally increased the bone volume but it could not completely rescue the osteopenia in the DMP1-GsalphaKO mice. Taken together, this data suggests that Gsalpha signaling in osteocytes leads to osteopenia driven, at least in part, by increased secretion of sclerostin. |
