Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification(HO).Understanding accessory factors modulating BMP signaling would provide both a means of ...Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification(HO).Understanding accessory factors modulating BMP signaling would provide both a means of enhancing BMP-dependent regeneration while preventing HO.This study focuses on the ability of the collagen receptor,discoidin domain receptor 2(DDR2),to regulate BMP activity.As will be shown,induction of bone formation by subcutaneous BMP2 implants is severely compromised in Ddr2-deficient mice.In addition,Ddr2 deficiency attenuates HO in mice expressing the ACVR1 mutation associated with human fibrodysplasia ossificans progressiva.In cells migrating into BMP2 implants,DDR2 is co-expressed with GLI1,a skeletal stem cell marker,and DDR2/GLI1-positive cells participate in BMP2-induced bone formation where they contribute to chondrogenic and osteogenic lineages.Consistent with this distribution,conditional knockout of Ddr2 in Gli1-expressing cells inhibited bone formation to the same extent seen in globally Ddr2-deficient animals.This response was explained by selective inhibition of Gli1+cell proliferation without changes in apoptosis.The basis for this DDR2 requirement was explored further using bone marrow stromal cells.Although Ddr2 deficiency inhibited BMP2-dependent chondrocyte and osteoblast differentiation and in vivo,bone formation,early BMP responses including SMAD phosphorylation remained largely intact.Instead,Ddr2 deficiency reduced the nuclear/cytoplasmic ratio of the Hippo pathway intermediates,YAP and TAZ.This suggests that DDR2 regulates Hippo pathway-mediated responses to the collagen matrix,which subsequently affect BMP responsiveness.In summary,DDR2 is an important modulator of BMP signaling and a potential therapeutic target both for enhancing regeneration and treating HO.展开更多
Discoidin Domain Receptor 2(DDR2)is a collagen-activated receptor kinase that,together with integrins,is required for cells to respond to the extracellular matrix.Ddr2 loss-of-function mutations in humans and mice cau...Discoidin Domain Receptor 2(DDR2)is a collagen-activated receptor kinase that,together with integrins,is required for cells to respond to the extracellular matrix.Ddr2 loss-of-function mutations in humans and mice cause severe defects in skeletal growth and development.However,the cellular functions of Ddr2 in bone are not understood.Expression and lineage analysis showed selective expression of Ddr2 at early stages of bone formation in the resting zone and proliferating chondrocytes and periosteum.Consistent with these findings,Ddr2^(+)cells could differentiate into hypertrophic chondrocytes,osteoblasts,and osteocytes and showed a high degree of colocalization with the skeletal progenitor marker,Gli1.A conditional deletion approach showed a requirement for Ddr2 in Gli1-positive skeletal progenitors and chondrocytes but not mature osteoblasts.Furthermore,Ddr2 knockout in limb bud chondroprogenitors or purified marrow-derived skeletal progenitors inhibited chondrogenic or osteogenic differentiation,respectively.This work establishes a cell-autonomous function for Ddr2 in skeletal progenitors and cartilage and emphasizes the critical role of this collagen receptor in bone development.展开更多
基金Scientific Research Training Program for Young Talents of Union Hospital,Tongji Medical College,Huazhong University of Science and Technology(F.W.),NIH/NIDCR grants DE029012 and DE029465Department of Defense Grant PR190899(R.T.F.)Michigan Musculoskeletal Health Core Center(NIH/NIAMS P30 AR069620)。
文摘Bone morphogenetic proteins are essential for bone regeneration/fracture healing but can also induce heterotopic ossification(HO).Understanding accessory factors modulating BMP signaling would provide both a means of enhancing BMP-dependent regeneration while preventing HO.This study focuses on the ability of the collagen receptor,discoidin domain receptor 2(DDR2),to regulate BMP activity.As will be shown,induction of bone formation by subcutaneous BMP2 implants is severely compromised in Ddr2-deficient mice.In addition,Ddr2 deficiency attenuates HO in mice expressing the ACVR1 mutation associated with human fibrodysplasia ossificans progressiva.In cells migrating into BMP2 implants,DDR2 is co-expressed with GLI1,a skeletal stem cell marker,and DDR2/GLI1-positive cells participate in BMP2-induced bone formation where they contribute to chondrogenic and osteogenic lineages.Consistent with this distribution,conditional knockout of Ddr2 in Gli1-expressing cells inhibited bone formation to the same extent seen in globally Ddr2-deficient animals.This response was explained by selective inhibition of Gli1+cell proliferation without changes in apoptosis.The basis for this DDR2 requirement was explored further using bone marrow stromal cells.Although Ddr2 deficiency inhibited BMP2-dependent chondrocyte and osteoblast differentiation and in vivo,bone formation,early BMP responses including SMAD phosphorylation remained largely intact.Instead,Ddr2 deficiency reduced the nuclear/cytoplasmic ratio of the Hippo pathway intermediates,YAP and TAZ.This suggests that DDR2 regulates Hippo pathway-mediated responses to the collagen matrix,which subsequently affect BMP responsiveness.In summary,DDR2 is an important modulator of BMP signaling and a potential therapeutic target both for enhancing regeneration and treating HO.
基金supported by a scholarship from the Ministry of Higher Education and Scientific Research, Libyan Transitional Government (FFM)a scholarship from King Saud University (AB), NIH/NIDCR grants DE11723, DE029012, DE029465+1 种基金Department of Defense grant PR190899, research funds from the Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry (to RTF)the Michigan Musculoskeletal Health Core Center ((NIH/NIAMS P30 AR069620)
文摘Discoidin Domain Receptor 2(DDR2)is a collagen-activated receptor kinase that,together with integrins,is required for cells to respond to the extracellular matrix.Ddr2 loss-of-function mutations in humans and mice cause severe defects in skeletal growth and development.However,the cellular functions of Ddr2 in bone are not understood.Expression and lineage analysis showed selective expression of Ddr2 at early stages of bone formation in the resting zone and proliferating chondrocytes and periosteum.Consistent with these findings,Ddr2^(+)cells could differentiate into hypertrophic chondrocytes,osteoblasts,and osteocytes and showed a high degree of colocalization with the skeletal progenitor marker,Gli1.A conditional deletion approach showed a requirement for Ddr2 in Gli1-positive skeletal progenitors and chondrocytes but not mature osteoblasts.Furthermore,Ddr2 knockout in limb bud chondroprogenitors or purified marrow-derived skeletal progenitors inhibited chondrogenic or osteogenic differentiation,respectively.This work establishes a cell-autonomous function for Ddr2 in skeletal progenitors and cartilage and emphasizes the critical role of this collagen receptor in bone development.
