Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation

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Abstract

The c-Abl protein is a non-receptor tyrosine kinase involved in many aspects of mammalian development. c-Abl kinase is widely expressed, but high levels are found in hyaline cartilage in the adult, bone tissue in newborn mice, and osteoblasts and associated neovasculature at sites of endochondrial ossification in the fetus1,2. Mice homozygous for mutations in the gene encoding c-Abl (Abl) display increased perinatal mortality, reduced fertility, foreshortened crania and defects in the maturation of B cells in bone marrow3,4. Here we demonstrate that Abl−/− mice are also osteoporotic. The long bones of mutant mice contain thinner cortical bone and reduced trabecular bone volume. The osteoporotic phenotype is not due to accelerated bone turnover—both the number and activity of osteoclasts are similar to those of control littermates—but rather to dysfunctional osteoblasts. In addition, the rate of mineral apposition in the mutant animals is reduced. Osteoblasts from both stromal and calvarial explants showed delayed maturation in vitro as measured by expression of alkaline phosphatase (ALP), induction of mRNA encoding osteocalcin and mineral deposition.

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Figure 1: Abl−/− mice are osteoporotic.
Figure 2: Abl−/− osteoclasts are normal.
Figure 3: Bone marrow-derived Abl−/− osteoblasts are defective.
Figure 4: Differentiation of calvarial Abl−/− osteoblasts is defective.
Figure 5: c-Abl expression is upregulated during osteoblast differentiation.

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Acknowledgements

We thank P. Schwartzberg, P. Ducy, G. Karsenty, M. Sahni and R. Majeska for helpful discussions and technical advice, and Genetics Institute for BMPs 2 and 4. S.L.T was supported by grants DE05413 and AR32788 from Shriner's Hospital for Crippled Children. M.M.T. was supported by a grant AR44089 from NIH. B.L. is an associate, S.B. a research assistant and S.P.G. an investigator of Howard Hughes Medical Institute.

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Correspondence to Stephen P. Goff.

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Li, B., Boast, S., de los Santos, K. et al. Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation. Nat Genet 24, 304–308 (2000) doi:10.1038/73542

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