Bone morphogenetic proteins(Bmp) are well-known to induce bone formation following chondrogenesis,but the direct role of Bmp signaling in the osteoblast lineage is not completely understood. We have recently shown tha...Bone morphogenetic proteins(Bmp) are well-known to induce bone formation following chondrogenesis,but the direct role of Bmp signaling in the osteoblast lineage is not completely understood. We have recently shown that deletion of the receptor Bmpr1 a in the osteoblast lineage with Dmp1-Cre reduces osteoblast activity in general but stimulates proliferation of preosteoblasts specifically in the cancellous bone region,resulting in diminished periosteal bone growth juxtaposed with excessive cancellous bone formation.Because expression of sclerostin(SOST), a secreted Wnt antagonist, is notably reduced in the Bmpr1 adeficient osteocytes, we have genetically tested the hypothesis that increased Wnt signaling might mediate the increase in cancellous bone formation in response to Bmpr1 a deletion. Forced expression of human SOST from a Dmp1 promoter fragment partially rescues preosteoblast hyperproliferation and cancellous bone overgrowth in the Bmpr1 a mutant mice, demonstrating functional interaction between Bmp and Wnt signaling in the cancellous bone compartment. To test whether increased Wnt signaling can compensate for the defect in periosteal growth caused by Bmpr1 a deletion, we have generated compound mutants harboring a hyperactive mutation(A214 V) in the Wnt receptor Lrp5. However, the mutant Lrp5 does not restore periosteal bone growth in the Bmpr1 a-deficient mice. Thus, Bmp signaling restricts cancellous bone accrual partly through induction of SOST that limits preosteoblast proliferation, but promotes periosteal bone growth apparently independently of Wnt activation.展开更多
There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as ...There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as a promising target pathway for developing novel bone anabolic drugs. Although neutralizing antibodies against the Wnt antagonist sclerostin have been tested,Wnt ligands themselves have not been fully explored as a potential therapy. Previous work has demonstrated Wnt7b as an endogenous ligand upregulated during osteoblast differentiation, and that Wnt7b overexpression potently stimulates bone accrual in the mouse. The earlier studies however did not address whether Wnt7b could promote bone formation when specifically applied to aged or fractured bones. Here we have developed a doxycycline-inducible strategy where Wnt7b is temporally induced in the bones of aged mice or during fracture healing. We report that forced expression of Wnt7b for 1 month starting at 15 months of age greatly stimulated trabecular and endosteal bone formation, resulting in a marked increase in bone mass. We further tested the effect of Wnt7b on bone healing in a murine closed femur fracture model. Induced expression of Wnt7b at the onset of fracture did not affect the initial cartilage formation but promoted mineralization of the subsequent bone callus. Thus, targeted delivery of Wnt7b to aged bones or fracture sites may be explored as a potential therapy.展开更多
基金supported by NIH grants AR060456 and AR055923(FL)partly supported by P30 AR057235(Washington University Musculoskeletal Research Center)+1 种基金supported by the George O’Brien Center for Kidney Disease Research(P30 DK079333)Kidney translational Research Core and the Renal Division at the Washington University School of Medicine
文摘Bone morphogenetic proteins(Bmp) are well-known to induce bone formation following chondrogenesis,but the direct role of Bmp signaling in the osteoblast lineage is not completely understood. We have recently shown that deletion of the receptor Bmpr1 a in the osteoblast lineage with Dmp1-Cre reduces osteoblast activity in general but stimulates proliferation of preosteoblasts specifically in the cancellous bone region,resulting in diminished periosteal bone growth juxtaposed with excessive cancellous bone formation.Because expression of sclerostin(SOST), a secreted Wnt antagonist, is notably reduced in the Bmpr1 adeficient osteocytes, we have genetically tested the hypothesis that increased Wnt signaling might mediate the increase in cancellous bone formation in response to Bmpr1 a deletion. Forced expression of human SOST from a Dmp1 promoter fragment partially rescues preosteoblast hyperproliferation and cancellous bone overgrowth in the Bmpr1 a mutant mice, demonstrating functional interaction between Bmp and Wnt signaling in the cancellous bone compartment. To test whether increased Wnt signaling can compensate for the defect in periosteal growth caused by Bmpr1 a deletion, we have generated compound mutants harboring a hyperactive mutation(A214 V) in the Wnt receptor Lrp5. However, the mutant Lrp5 does not restore periosteal bone growth in the Bmpr1 a-deficient mice. Thus, Bmp signaling restricts cancellous bone accrual partly through induction of SOST that limits preosteoblast proliferation, but promotes periosteal bone growth apparently independently of Wnt activation.
基金supported by AR060456 (F.L.), AR047867 (M.J.S.)the Washington University Musculoskeletal Research Center (NIH P30 AR057235)
文摘There remain unmet clinical needs for safe and effective bone anabolic therapies to treat aging-related osteoporosis and to improve fracture healing in cases of nonunion or delayed union. Wnt signaling has emerged as a promising target pathway for developing novel bone anabolic drugs. Although neutralizing antibodies against the Wnt antagonist sclerostin have been tested,Wnt ligands themselves have not been fully explored as a potential therapy. Previous work has demonstrated Wnt7b as an endogenous ligand upregulated during osteoblast differentiation, and that Wnt7b overexpression potently stimulates bone accrual in the mouse. The earlier studies however did not address whether Wnt7b could promote bone formation when specifically applied to aged or fractured bones. Here we have developed a doxycycline-inducible strategy where Wnt7b is temporally induced in the bones of aged mice or during fracture healing. We report that forced expression of Wnt7b for 1 month starting at 15 months of age greatly stimulated trabecular and endosteal bone formation, resulting in a marked increase in bone mass. We further tested the effect of Wnt7b on bone healing in a murine closed femur fracture model. Induced expression of Wnt7b at the onset of fracture did not affect the initial cartilage formation but promoted mineralization of the subsequent bone callus. Thus, targeted delivery of Wnt7b to aged bones or fracture sites may be explored as a potential therapy.
