Research article

Dominant negative Bmp5 mutation reveals key role of BMPs in skeletal response to mechanical stimulation

Andrew M Ho¹ , Paul C Marker² , Hairong Peng¹ , Andres J Quintero¹ , David M Kingsley³ and Johnny Huard^1,4

¹Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA

²Department of Genetics, Cell Biology, and Development, University of Minnesota Cancer Center, MMC 806, 420 Delaware St. SE, Minneapolis, Minnesota 55455, USA

³Department of Developmental Biology and Howard Hughes Medical Institute, Beckman Center B300, Stanford University School of Medicine, Stanford, California 94305, USA

⁴Departments of Molecular Genetics and Biochemistry and Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA

author email corresponding author email

BMC Developmental Biology 2008, 8:35doi:10.1186/1471-213X-8-35

Published:	1 April 2008

Abstract

Background

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. 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.

Results

Here, 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.

Conclusion

The 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.