ARS | Publication request: Transgenic overexpression of bone morphogenetic protein 11 propeptide in skeleton enhances bone formation

Submitted to: Biochemical and Biophysical Research Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 30, 2011
Publication Date: December 16, 2011
Citation: Li, Z., Zeng, F., Mitchell, A.D., Kim, Y., Wu, Z., Yang, J. 2011. Transgenic overexpression of bone morphogenetic protein 11 propeptide in skeleton enhances bone formation. Biochemical and Biophysical Research Communications. 416(3-4):289-92.

Interpretive Summary: Bone morphogenetic proteins (BMPs) are a group of regulatory proteins that participate in various biological processes such as embryonic skeletal patterning, postnatal bone formation and metabolism. To evaluate the roles of BMP11 propeptide in skeletal development in vivo, we generated transgenic mice that over-express BMP11 propeptide under the control of a bone-specific regulatory element, the 2.3 kb a1 type 1 collagen promoter. These transgenic mice were viable and fertile, but exhibited abnormal patterning of axial skeleton with transformation of the seventh cervical vertebra into a thoracic vertebra by forming ectopic ribs on the seventh cervical vertebra. The transgene mRNA was detectable in tail tissue at 12.5 days post conception (dpc) and later times (14.5 and 16.5 dpc). The transgene mRNA expression was detected in bone and several other tissues. A further characterization of the transgenic mice in the present study shows that skeletal- specific expression of the BMP11 propeptide cDNA significantly increased skeletal formation and expression levels of several osteoblast marker genes. The results suggest that over-expression of BMP11 propeptide stimulates bone formation by increasing osteoblast (bone forming) cell functions.

Technical Abstract: Bone morphogenetic protein 11 (BMP11) is a key regulatory protein in skeletal development. BMP11 propeptide has been shown to antagonize GDF11 activity in vitro. To explore the role of BMP11 propeptide in skeletal formation in vivo, we generated transgenic mice with skeleton-specific overexpression of BMP11 propeptide cDNA. The mice showed a transformation of the seventh cervical vertebra into a thoracic vertebra in our previous report. Presently, further characterizations of the transgenic mice indicated that ossification in calvatia was dramatically enhanced in transgenic fetuses at 16.5 days post conception (dpc) in comparison with their wild-type littermates. At 10 weeks of age, bone mineral content and bone mineral density were significantly (P<0.05) higher in transgenic mice than that in their wild-type littermates based on dual energy X-ray absorptiometry analysis. The relative trabecular bone volume measured by histological analysis was dramatically increased in transgenic mice compared with their wild-type littermates. The enhanced bone formations in the transgenic mice appear to result from increase osteoblast activities as the expressions of four osteoblast markers ' a 1 type 1 collagen, osteocalcin, alkaline phosphatase and phex were significantly higher in transgenic fetuses than that in their wild-type littermates. These results suggest that over-expression of BMP11 propeptide stimulates bone formation by increasing osteoblast cell functions.