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 cond...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.展开更多
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 ro...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.展开更多
Mechanical loading opens connexin 43(Cx43)hemichannels(HCs),leading to the release of bone anabolic molecules,such as prostaglandins,from mechanosensitive osteocytes,which is essential for bone formation and remodelin...Mechanical loading opens connexin 43(Cx43)hemichannels(HCs),leading to the release of bone anabolic molecules,such as prostaglandins,from mechanosensitive osteocytes,which is essential for bone formation and remodeling.However,the mechanotransduction mechanism that activates HCs remains elusive.Here,we report a unique pathway by which mechanical signals are effectively transferred between integrin molecules located in different regions of the cell,resulting in HC activation.Both integrinα5 andαV were activated upon mechanical stimulation via either fluid dropping or flow shear stress(FSS).Inhibition of integrinαV activation or ablation of integrinα5 prevented HC opening on the cell body when dendrites were mechanically stimulated,suggesting mechanical transmission from the dendritic integrinαV toα5 in the cell body during HC activation.In addition,HC function was compromised in vivo,as determined by utilizing an antibody blockingαV activation andα5-deficient osteocyte-specific knockout mice.Furthermore,inhibition of integrinαV activation,but not that ofα5,attenuated activation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT)signaling pathway upon mechanical loading,and the inhibition of PI3K/AKT activation blocked integrinα5 activation and HC opening.Moreover,HC opening was blocked only by an anti-integrinαV antibody at low but not high FSS levels,suggesting that dendriticαV is a more sensitive mechanosensor thanα5 for activating HCs.Together,these results reveal a new molecular mechanism of mechanotransduction involving the coordinated actions of integrins and PI3K/AKT in osteocytic dendritic processes and cell bodies that leads to HC opening and the release of key bone anabolic factors.展开更多
基金supported by the National Institutes of Health(NIH)Grants:AR072020(to J.X.J.)Welch Foundation grant:AQ-1507(to J.X.J.).
文摘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.
基金supported by NIH grants,AR072020 and CA196214Welch Foundation grant AQ-1507 to J.X.J.+1 种基金China Scholarship Council funding to L.M.Micro-CT imaging was completed at RAYO,the Daniel Carlisle Center for Bone and Mineral Imaging at the University of Texas Health Science Center at San AntonioRAYO is supported by an equipment grant.R.J.F. was supported by NIH grant RR025687
文摘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.
基金the National Institutes of Health(NIH)grant AR072072(to J.X.J.)the Welch Foundation grant AQ-1507(to J.X.J.).We also thank the UTHSCSA CMMI and the UTHSCSA Optical Imaging Facility supported by the Cancer Therapy and Research Center for the support provided from the NIH-National Cancer Institute P30 award CA054174 and Texas state funds.
文摘Mechanical loading opens connexin 43(Cx43)hemichannels(HCs),leading to the release of bone anabolic molecules,such as prostaglandins,from mechanosensitive osteocytes,which is essential for bone formation and remodeling.However,the mechanotransduction mechanism that activates HCs remains elusive.Here,we report a unique pathway by which mechanical signals are effectively transferred between integrin molecules located in different regions of the cell,resulting in HC activation.Both integrinα5 andαV were activated upon mechanical stimulation via either fluid dropping or flow shear stress(FSS).Inhibition of integrinαV activation or ablation of integrinα5 prevented HC opening on the cell body when dendrites were mechanically stimulated,suggesting mechanical transmission from the dendritic integrinαV toα5 in the cell body during HC activation.In addition,HC function was compromised in vivo,as determined by utilizing an antibody blockingαV activation andα5-deficient osteocyte-specific knockout mice.Furthermore,inhibition of integrinαV activation,but not that ofα5,attenuated activation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT)signaling pathway upon mechanical loading,and the inhibition of PI3K/AKT activation blocked integrinα5 activation and HC opening.Moreover,HC opening was blocked only by an anti-integrinαV antibody at low but not high FSS levels,suggesting that dendriticαV is a more sensitive mechanosensor thanα5 for activating HCs.Together,these results reveal a new molecular mechanism of mechanotransduction involving the coordinated actions of integrins and PI3K/AKT in osteocytic dendritic processes and cell bodies that leads to HC opening and the release of key bone anabolic factors.