Expression of endogenous BMP-2 in periosteal progenitor cells is essential for bone healing.
Bone morphogenic protein 2 (BMP-2) plays a key role in skeletal development, repair and regeneration. To gain a better understanding of the role of BMP-2 in periosteum-mediated bone repair, we deleted BMP-2 postnatally at the initiation stage of healing utilizing a Tamoxifen-inducible CreER mouse model. To mark the mutant cells, we further generated a BMP-2(f/f); CreER; RosaR mouse model that enabled the activation of a LacZ reporter gene upon treatment of Tamoxifen. We demonstrated that deletion of BMP-2 at the onset of healing abolished periosteum-mediated bone/cartilage callus formation. In a chimeric periosteal callus with cells derived from both wild type and the mutant, over 90% of the mutant mesenchymal progenitors remained undifferentiated. Within differentiated bone and cartilage tissues, only a few cells could be identified as mutants. Using a bone graft transplantation approach, we further showed that transplantation of a mutant bone graft into a wild type host failed to rescue the deficient differentiation of the mutant cells at day 10 post-grafting. These data strongly suggest that the endogenous expression of BMP-2 plays a critical role in osteogenic and chondrogenic differentiation of periosteal progenitors during repair. To determine whether BMP-2 deficient cells remained responsive to exogenous BMP-2, we isolated periosteal mesenchymal progenitors from BMP-2 deficient bone autografts. The isolated cells demonstrated a 90% reduction of endogenous BMP-2 expression, accompanied by significant decrease in cellular proliferation and a near blockade of osteogenic differentiation. The addition of exogenous BMP-2 partially rescued impaired proliferation and further enhanced osteogenic differentiation in a dose dependent manner. Taken together, our data show that the initiation of the cortical bone repair in vivo is controlled by endogenous BMP-2. Future studies are necessary to determine the mechanisms by which the BMP-2 pathway is activated in periosteal progenitor cells at the onset of cortical bone repair.
Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642, USA.
Qun
Q
Wang
Chunlan
C
Huang
Ming
M
Xue
Xinping
X
Zhang
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D016025:Bone Transplantation; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D020219:Chondrogenesis; D017353:Gene Deletion; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010012:Osteogenesis; D010521:Periosteum / Q000166:cytology*; D013997:Time Factors; D014945:Wound Healing
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2