Adult bone structural integrity is maintained by remodeling via the coupling of osteoclastic bone resorption and osteoblastic bone formation.Osteocytes or osteoblasts express receptor activator of nuclear factor k-B l...Adult bone structural integrity is maintained by remodeling via the coupling of osteoclastic bone resorption and osteoblastic bone formation.Osteocytes or osteoblasts express receptor activator of nuclear factor k-B ligand(Rankl)or osteoprotegerin(Opg)to promote or inhibit osteoclastogenesis,respectively.Bone morphogenetic protein(BMP)is a potent bone inducer,but its major role in adult bone is to induce osteocytes to upregulate sclerostin(Sost)and increase the Rankl/Opg expression ratio,resulting in promotion of osteoclastogenesis.However,the precise effect of BMP-target gene(s)in osteoblasts on the Rankl/Opg expression ratio remains unclear.In the present study,we identified atonal homolog 8(Atoh8),which is directly upregulated by the BMPSmadl axis in osteoblasts.In vivo,Atoh8 was detected in osteoblasts but not osteocytes in adult mice.Although global Atoh8-knockout mice showed only a mild phenotype in the neonate skeleton,the bone volume was decreased and osteoclasts were increased in the adult phase.Atoh8-null marrow stroma cells were more potent than wild-type cells in inducing osteoclastogenesis in marrow cells.Atoh8 loss in osteoblasts increased Runx2 expression and the Rankl/Opg expression ratio,while Runx2 knockdown normalized the Rankl/Opg expression ratio.Moreover,Atoh8 formed a protein complex with Runx2 to inhibit Runx2 transcriptional activity and decrease the Rankl/Opg expression ratio.These results suggest that bone remodeling is regulated elaborately by BMP signaling;while BMP primarily promotes bone resorption,it simultaneously induces Atoh8 to inhibit Runx2 and reduce the Rankl/Opg expression ratio in osteoblasts,suppressing osteoclastogenesis and preventing excessive BMP-mediated bone resorption.展开更多
Exosomes make a significant contribution during stem cell-based therapy due to the abundant contents.Accumulating evidence implies exosomes can act as potential biological nano agents.We herein propose hypoxic precond...Exosomes make a significant contribution during stem cell-based therapy due to the abundant contents.Accumulating evidence implies exosomes can act as potential biological nano agents.We herein propose hypoxic preconditioning for neural stem cells(NSCs)that could produce hypoxic exosomes for efficient treatment of ischemic stroke.Hypoxic preconditioning on NSCs significantly altered the miRNAs encapsulated in exosomes.Notably,hypoxic exosomes could target the injured brain to regulate the microenvironment to inhibit neuroinflammation and promote blood–brain barrier permeability recovery.Additionally,the autologous NSCs in Nestin-CreER mice could be activated by hypoxic exosomes to facilitate nerve regeneration.After hypoxic preconditioning,exosomes further exerted therapeutic effects on both survival(25%)and behavioral outcomes in ischemic stroke mice.Overall,hypoxic preconditioning NSCs can produce effective nano agent and may represent a promising strategy for clinical neurorestorative therapy.展开更多
Heterotopic ossification(HO)describes bone formation at non-skeletal sites and results from traumatic injury,surgery,or genetic disease such as fibrodysplasia ossificans progressiva(FOP).1,2 Although it is known that ...Heterotopic ossification(HO)describes bone formation at non-skeletal sites and results from traumatic injury,surgery,or genetic disease such as fibrodysplasia ossificans progressiva(FOP).1,2 Although it is known that BMP signaling regulates HO,knowledge about the developmental origin of the osteogenic progenitors responsible for the BMP-associated metamorphosis is comparably less.With the use of transgenic mice and labelled neural crest-derived cell,3 we found myelin protein zero(P0,or MPZ)-and Wnt1-lineage cells give rise to BMP-7 induced adult ectopic cartilage and bone.展开更多
基金This study was supported by research grants from the Japan Society for the Promotion of Science,KAKENHI:grant-in-aid for scientific research(C)(grant Nos.15K10486,17K10933,and 18K09111).We thank K.Yuki(the University of Tokyo)for mouse careHui Gao for technical assistance+1 种基金Isozo,Inc.for bone histomorphometry andμ-CT analysesand Bio Matrix Research Inc.for microarray analysis.
文摘Adult bone structural integrity is maintained by remodeling via the coupling of osteoclastic bone resorption and osteoblastic bone formation.Osteocytes or osteoblasts express receptor activator of nuclear factor k-B ligand(Rankl)or osteoprotegerin(Opg)to promote or inhibit osteoclastogenesis,respectively.Bone morphogenetic protein(BMP)is a potent bone inducer,but its major role in adult bone is to induce osteocytes to upregulate sclerostin(Sost)and increase the Rankl/Opg expression ratio,resulting in promotion of osteoclastogenesis.However,the precise effect of BMP-target gene(s)in osteoblasts on the Rankl/Opg expression ratio remains unclear.In the present study,we identified atonal homolog 8(Atoh8),which is directly upregulated by the BMPSmadl axis in osteoblasts.In vivo,Atoh8 was detected in osteoblasts but not osteocytes in adult mice.Although global Atoh8-knockout mice showed only a mild phenotype in the neonate skeleton,the bone volume was decreased and osteoclasts were increased in the adult phase.Atoh8-null marrow stroma cells were more potent than wild-type cells in inducing osteoclastogenesis in marrow cells.Atoh8 loss in osteoblasts increased Runx2 expression and the Rankl/Opg expression ratio,while Runx2 knockdown normalized the Rankl/Opg expression ratio.Moreover,Atoh8 formed a protein complex with Runx2 to inhibit Runx2 transcriptional activity and decrease the Rankl/Opg expression ratio.These results suggest that bone remodeling is regulated elaborately by BMP signaling;while BMP primarily promotes bone resorption,it simultaneously induces Atoh8 to inhibit Runx2 and reduce the Rankl/Opg expression ratio in osteoblasts,suppressing osteoclastogenesis and preventing excessive BMP-mediated bone resorption.
基金the National Natural Science Foundation of China(Nos.U22A20383 and 82003668)the Natural Science Foundation of Zhejiang Province(Nos.LD22H300002 and LQ21H300002)+2 种基金China Postdoctoral Science Foundation(No.2020M671771)Ningbo Technology Innovation 2025 Major Special Project(No.2022Z150)the innovative team of acupuncture and Chinese herbal medicine for prevention and treatment of senile neurodegenerative diseases.
文摘Exosomes make a significant contribution during stem cell-based therapy due to the abundant contents.Accumulating evidence implies exosomes can act as potential biological nano agents.We herein propose hypoxic preconditioning for neural stem cells(NSCs)that could produce hypoxic exosomes for efficient treatment of ischemic stroke.Hypoxic preconditioning on NSCs significantly altered the miRNAs encapsulated in exosomes.Notably,hypoxic exosomes could target the injured brain to regulate the microenvironment to inhibit neuroinflammation and promote blood–brain barrier permeability recovery.Additionally,the autologous NSCs in Nestin-CreER mice could be activated by hypoxic exosomes to facilitate nerve regeneration.After hypoxic preconditioning,exosomes further exerted therapeutic effects on both survival(25%)and behavioral outcomes in ischemic stroke mice.Overall,hypoxic preconditioning NSCs can produce effective nano agent and may represent a promising strategy for clinical neurorestorative therapy.
基金supported by grants-in-aid for scientific research from the Japan Society for the Promotion of Science(JSPS)(No.16K15662)iPS Cell Research Fund(No.200154400002)+2 种基金Suzuken Memorial Foundation(No.21-008),the Core Center for iPS Cell Research of the Research Center Network for Realization of Regenerative Medicine(No.21bm0104001h0009)the Practical Research Project for Rare/Intractable Diseases(No.16ek0109161h0002)from the Japan Agency for Medical Research and Development(AMED)to MIThis work was also supported by grants-in-aid for scientific research from JSPS(No.19K16540 and 21K06855)to CZ.
文摘Heterotopic ossification(HO)describes bone formation at non-skeletal sites and results from traumatic injury,surgery,or genetic disease such as fibrodysplasia ossificans progressiva(FOP).1,2 Although it is known that BMP signaling regulates HO,knowledge about the developmental origin of the osteogenic progenitors responsible for the BMP-associated metamorphosis is comparably less.With the use of transgenic mice and labelled neural crest-derived cell,3 we found myelin protein zero(P0,or MPZ)-and Wnt1-lineage cells give rise to BMP-7 induced adult ectopic cartilage and bone.