Connexin 43 hemichannels protect bone loss during estrogen deficiency

Estrogen deficiency in postmenopausal women is a major cause of bone loss,resulting in osteopenia,osteoporosis,and a high risk for bone fracture.Connexin 43 (Cx43) hemichannels (HCs) in osteocytes play an important role in osteocyte viability,bone formation,and remodeling.We showed here that estrogen deficiency reduced Cx43 expression and HC function.To determine if functional HCs protect osteocytes and bone loss during estrogen deficiency,we adopted an ovariectomy model in wild-type (WT) and two transgenic Cx43 mice:R76W (dominant-negative mutant inhibiting only gap junction channels) and Cx43 Δ130–136 (dominant-negative mutant compromising both gap junction channels and HCs).The bone mineral density (BMD),bone structure,and histomorphometric changes of cortical and trabecular bones after ovariectomy were investigated.Our results showed that the Δ130–136 transgenic cohort had greatly decreased vertebral trabecular bone mass compared to WT and R76W mice,associated with a significant increase in the number of apoptotic osteocyte and empty lacunae.Moreover,osteoclast surfaces in trabecular and cortical bones were increased after ovariectomy in the R76W and WT mice,respectively,but not in Δ130–136 mice.These data demonstrate that impairment of Cx43 HCs in osteocytes accelerates vertebral trabecular bone loss and increase in osteocyte apoptosis,and further suggest that Cx43 HCs in osteocytes protect trabecular bone against catabolic effects due to estrogen deficiency.

Osteocytes regulate bone anabolic response to mechanical loading in male mice via activation of integrinα5

Physical mechanical stimulation can maintain and even increase bone mass.Here,we report an important role of osteocytic integrinα5 in regulating the anabolic response of bone to mechanical loading using an Itga5 conditional gene knockout(cKO)mouse model.Integrinα5 gene deletion increased apoptotic osteocytes and reduced cortical anabolic responses to tibial compression including decreased endosteal osteoblasts and bone formation,and increased endosteal osteoclasts and bone resorption,contributing to the decreased bone area fraction and biomechanical properties,leading to an enlarged bone marrow area in cKO mice.Similar disruption of anabolic responses to mechanical loading was also detected in cKO trabecular bone.Moreover,integrinα5 deficiency impeded load-induced Cx43 hemichannel opening,and production and release of PGE2,an anabolic factor,resulting in attenuated effects of the loading on catabolic sclerostin(SOST)reduction and anabolicβ-catenin increase.Together,this study shows an indispensable role of integrinα5 in osteocytes in the anabolic action of mechanical loading on skeletal tissue through activation of hemichannels and PGE2-evoked gene expression.Integrinα5 could act as a potential new therapeutic target for bone loss,especially in the elderly population with impeded mechanical sensitivity.