Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation.
Although accumulated evidence has shown the bone anabolic effects of bone morphogenetic proteins (BMPs) that were exogenously applied in vitro and in vivo, the roles of endogenous BMPs during bone formation remain to be clarified. This study initially investigated expression patterns of BMPs in the mouse long bone and found that BMP2 and BMP6 were the main subtypes expressed in hypertrophic chondrocytes that induce endochondral bone formation. We then examined the involvement of the combination of these BMPs in bone formation in vivo by generating the compound-deficient mice (Bmp2+/-;Bmp6-/-). Under physiological conditions, these mice exhibited moderate growth retardation compared with the wild-type (WT) littermates during the observation period up to 52 weeks of age. Both the fetal and adult compound-deficient mice showed a reduction in the trabecular bone volume with suppressed bone formation, but normal bone resorption, whereas the single deficient mice (Bmp2+/- or Bmp6-/-) did not. When a fracture was created at the femoral midshaft and the bone healing was analyzed, the endochondral bone formation, but not intramembranous bone formation, was impaired by the compound deficiency. In the cultures of bone marrow cells, however, there was no difference in osteogenic differentiation between WT and compound-deficient cells in the presence or absence of the exogenous BMP2. We thus concluded that endogenous BMP2 and BMP6 cooperatively play pivotal roles in bone formation under both physiological and pathological conditions.
Kugimiya
Fumitaka
F
Division of Tissue Engineering, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo, 113-8655, Japan.
Kawaguchi
Hiroshi
H
Kamekura
Satoru
S
Chikuda
Hirotaka
H
Ohba
Shinsuke
S
Yano
Fumiko
F
Ogata
Naoshi
N
Katagiri
Takenobu
T
Harada
Yoshifumi
Y
Azuma
Yoshiaki
Y
Nakamura
Kozo
K
Chung
Ung-il
UI
D000818:Animals; D001835:Body Weight; D015519:Bone Density; D001846:Bone Development; D001854:Bone Marrow Cells / Q000166:cytology; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000502:physiology*; D001842:Bone and Bones / Q000196:embryology* / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D019902:Chondrocytes / Q000378:metabolism; D019281:Dimerization; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*
C525719:Bmp2 protein, mouse; C525817:Bmp6 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta