Osteoblast-specific Knockout Of The TGFBR2 Gene Results In Early Onset Osteoporosis In Mice

Transforming growth factor-β(TGF-β) signaling pathway plays important roles in regulating cell proliferation, differentiation, migration and apoptosis in a broad spectrum of tissues and organ systems. TGF-βligands express abundantly in bone tissues and have dramatic effects on the bone cells responsible for bone formation and resorption. TGF-βmay act as a bone-coupling factor linking bone formation to bone resorption in skeletal development and bone remodeling. It has been previously shown that disruption of osteoblastic responsiveness to TGF-βin transgenic mice by expressing a cytoplasmically truncated type II TGF-βreceptor (TGFBR2) from the osteocalcin promoter leads to decreased bone remodeling and increased trabecular bone mass. And osteoblast-specific knockout of the Smad4 gene, which is a central mediator of TGF-βsignaling pathway, results in an early onset osteoporosis. To further explore the precise mechanism of TGF-βsignaling in maintaining bone homeostasis, an osteoblast-specific TGFBR2 gene knockout mouse was generated using the Cre-loxP system. In this study, mutant mice were phenotypically normal at birth and developed growth retardation 2 weeks later. Soft X-ray and bone mineral density analysis demonstrated a dramatically decreased bone mineral density in the early life of mutant mice.μ-CT and bone histomorphometric analysis showed that bone trabecular volume and bone formation decreased in mutant mice. In addition, the serum alkaline phosphatase (ALP) level was significantly decreased in mutant mice. On the other hand, abolish of TGFBR2 gene in differentiated osteoblast resulted in decreased osteoclast number and bone resorption.These data showed that TGFBR2 mutant mice developed low turnover osteoporosis. Primary osteoblasts culture systems in vitro showed that TGFBR2 deficiency in osteoblasts caused two autonomous abnormalities: accelerated differentiation and increased susceptibility to apoptosis. Our results provide genetic evidence to demonstrate that osteoblastic TGFBR2 plays an important role in maintaining bone homeostasis in vivo and in vitro. The altered responsiveness of osteoblasts to TGF-βdue to the loss of TGFBR2 leads to defective bone remodeling and osteoporosis. The mouse model generated by disruption of TGFBR2 gene in osteoblast could be used for further studies on the molecular mechanism of TGF-βsignaling in the maitainence of bone remodeling and homeostasis. The mouse model could also be used for screening the therapeutic targets and evaluating the treatments of osteoporosis.