Regulation of body length and bone mass by Gpr126/Adgrg6

Abstract

Adhesion G protein–coupled receptor G6 (Adgrg6; also named GPR126) single-nucleotide polymorphisms are associated with human height in multiple populations. However, whether and how GPR126 regulates body height is unknown. In this study, we found that mouse body length was specifically decreased in Osx-Cre;Gpr126fl/fl mice. Deletion of Gpr126 in osteoblasts resulted in a remarkable delay in osteoblast differentiation and mineralization during embryonic bone formation. Postnatal bone formation, bone mass, and bone strength were also significantly affected in Gpr126 osteoblast deletion mice because of defects in osteoblast proliferation, differentiation, and ossification. Furthermore, type IV collagen functioned as an activating ligand of Gpr126 to regulate osteoblast differentiation and function by stimulating cAMP signaling. Moreover,the cAMP activator PTH(1–34), could partially restore the inhibition of osteoblast differentiation and the body length phenotype induced by Gpr126 deletion.Together, our results demonstrated that COLIV-Gpr126 regulated body length and bone mass through cAMP-CREB signaling pathway.

A G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment

“…In contrast to a recent report (Sun et al, 2020), we found that Adgrg6 has no obvious functional role in bone forming osteoblasts for skeletal morphology. We observed no spinal malformations nor apparent limb or growth phenotype in either Oc-cKO mice or Sp7-cKO mice (Fig.…”

“…Sun et al . also reported that scoliosis was not present in OsxCre;Gpr126 f/f mice (equivalent to our Sp7-cKO mice) at P120 (Sun et al, 2020). However, in contrast with our findings, Sun et al .…”

“…reported that deletion of Adgrg6 ( Gpr126 ) with OsxCre , but not LysmCre (which targets osteoclast) or Col2Cre , resulted in a significant reduction in overall body size and the bone length. The authors attributed this effect primarily due to delayed osteoblast differentiation (Sun et al, 2020). We and others have shown that Col2Cre recombines in early osteochondral progenitor cells that give rise to both osteoblasts and chondrocytes (Liu et al, 2019; Long et al, 2001).…”

Subchondral bone microenvironment in osteoarthritis and pain

“…Hyaline cartilage is a nonvascularized tissue with resistance to vessel formation, but angiogenesis plays a critical role in endochondral bone formation, 94 , 95 suggesting that vessels might be responsible for cartilage digestion. Elegant research presented by Ramasamy et al 19 proved the proteolytic function of endothelial cells, which misdirected the orientation of growth plate type H vessel elongation in the proximal tibia.…”

“…Endothelial cells erode the cartilage matrix during bone elongation, thus creating space for substantial osteogenesis. 19 , 95 Specifically, endothelial cells present 40-fold increased MMP-9 expression compared with osteoclasts during entochondrostosis, and the conditional knockout of MMP-9 in the postnatal endothelium leads to osteogenic defects and abnormally large growth plates, suggesting a critical role of endothelial-derived MMP-9 in cartilage resorption. In addition, the intra-articular administration of VEGF can accelerate OA progression in rodent models, 116 while anti-VEGF treatment can ameliorate cartilage degradation.…”