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

Ho AM, Marker PC, Peng H, Quintero AJ, Kingsley DM, Huard J - BMC Dev. Biol. (2008)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Developmental Biology and Howard Hughes Medical Institute, Beckman Center B300, Stanford University School of Medicine, Stanford, California 94305, USA. andrewho@pitt.edu

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.

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Multiple Bmps are expressed at the deltoid tuberosity. In situ hybridization analysis of the developing deltoid tuberosity at embryonic day 13.5 with antisense probes to (a) collagen 2, (b) Bmp5, (c) Bmp2, or (d) Bmp6 shows expression of multiple Bmps at the developing deltoid tuberosity (arrowheads). Control sense probes did not detect any appreciable signal (data not shown).
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Figure 3: Multiple Bmps are expressed at the deltoid tuberosity. In situ hybridization analysis of the developing deltoid tuberosity at embryonic day 13.5 with antisense probes to (a) collagen 2, (b) Bmp5, (c) Bmp2, or (d) Bmp6 shows expression of multiple Bmps at the developing deltoid tuberosity (arrowheads). Control sense probes did not detect any appreciable signal (data not shown).

Mentions: The deltoid muscle remained present in Bmp5clv/Bmp5clv mutants, suggesting that the deltoid crest defect was likely due to changes in the humerus bone. In situ hybridization showed Bmp5 expression in the developing deltoid crest of the humerus (Fig. 3b), and coexpression of the Bmp2 and Bmp6 genes in similar regions (Fig. 3c, d). The coexpression of multiple Bmps may explain why the deltoid crest is only mildly reduced in Bmp5mice but completely eliminated in Bmp5clv mice. The expression of multiple Bmp genes at the deltoid crest and the defect of this structure in Bmp5clv mutants suggest that Bmp signaling is important at this mechanosensitive site.


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

Ho AM, Marker PC, Peng H, Quintero AJ, Kingsley DM, Huard J - BMC Dev. Biol. (2008)

Multiple Bmps are expressed at the deltoid tuberosity. In situ hybridization analysis of the developing deltoid tuberosity at embryonic day 13.5 with antisense probes to (a) collagen 2, (b) Bmp5, (c) Bmp2, or (d) Bmp6 shows expression of multiple Bmps at the developing deltoid tuberosity (arrowheads). Control sense probes did not detect any appreciable signal (data not shown).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2335095&req=5

Figure 3: Multiple Bmps are expressed at the deltoid tuberosity. In situ hybridization analysis of the developing deltoid tuberosity at embryonic day 13.5 with antisense probes to (a) collagen 2, (b) Bmp5, (c) Bmp2, or (d) Bmp6 shows expression of multiple Bmps at the developing deltoid tuberosity (arrowheads). Control sense probes did not detect any appreciable signal (data not shown).
Mentions: The deltoid muscle remained present in Bmp5clv/Bmp5clv mutants, suggesting that the deltoid crest defect was likely due to changes in the humerus bone. In situ hybridization showed Bmp5 expression in the developing deltoid crest of the humerus (Fig. 3b), and coexpression of the Bmp2 and Bmp6 genes in similar regions (Fig. 3c, d). The coexpression of multiple Bmps may explain why the deltoid crest is only mildly reduced in Bmp5mice but completely eliminated in Bmp5clv mice. The expression of multiple Bmp genes at the deltoid crest and the defect of this structure in Bmp5clv mutants suggest that Bmp signaling is important at this mechanosensitive site.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Developmental Biology and Howard Hughes Medical Institute, Beckman Center B300, Stanford University School of Medicine, Stanford, California 94305, USA. andrewho@pitt.edu

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.

Show MeSH
Related in: MedlinePlus