Abstract
BackgroundOver a hundred years ago, Wolff originally observed that bone growth and remodeling are exquisitely sensitive to mechanical forces acting on the skeleton. Clinical studies have noted that the size and the strength of bone increase with weight bearing and muscular activity and decrease with bed rest and disuse. Although the processes of mechanotransduction and functional response of bone to mechanical strain have been extensively studied, the molecular signaling mechanisms that mediate the response of bone cells to mechanical stimulation remain unclear.ResultsHere, we identify a novel germline mutation at the mouse Bone morphogenetic protein 5 (Bmp5) locus. Genetic analysis shows that the mutation occurs at a site encoding the proteolytic processing sequence of the BMP5 protein and blocks proper processing of BMP5. Anatomic studies reveal that this mutation affects the formation of multiple skeletal features including several muscle-induced skeletal sites in vivo. Biomechanical studies of osteoblasts from these anatomic sites show that the mutation inhibits the proper response of bone cells to mechanical stimulation.ConclusionThe results from these genetic, biochemical, and biomechanical studies suggest that BMPs are required not only for skeletal patterning during embryonic development, but also for bone response and remodeling to mechanical stimulation at specific anatomic sites in the skeleton.
Highlights
Over a hundred years ago, Wolff originally observed that bone growth and remodeling are exquisitely sensitive to mechanical forces acting on the skeleton
Cells transfected with the wild-type construct produced BMP5 protein bands of ~40 kDa and ~20 kDa, consistent with the expected sizes of the cleaved BMP5 pro and mature domains (Fig. 1d)
To further characterize the relationship between mechanical stimulation and Bone morphogenetic proteins (BMPs) signaling, we studied the effect of mechanical strain on cellular translocation of SMAD proteins, key transcription factors that translocate from the cytoplasm to the nucleus upon activation of BMP receptors [52]
Summary
Over a hundred years ago, Wolff originally observed that bone growth and remodeling are exquisitely sensitive to mechanical forces acting on the skeleton. Clinical studies have noted that the size and the strength of bone increase with weight bearing and muscular activity and decrease with bed rest and disuse. It has long been observed that bone mass and mineral density can be altered at very specific sites of the skeleton in response to mechanical stimulation during exercise, as seen in increased size and cortical thickness of the arm bone from the dominant side in tennis players [1,2,3] and the (page number not for citation purposes). Biomechanical studies show that mutant osteoblasts from these sites failed to respond appropriately to mechanical strain and may implicate BMPs as the endogenous signals for bone formation in response to mechanical stimulation
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