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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O'Neill, A.J., Cotter, T.G., Russell, J.M. & Gaffney, E.F. Abl expression in human fetal and adult tissues, tumours, and tumour microvessels . J. Pathol. 183, 325–329 (1997).
Muller, R., Slamon, D.J., Trembley, J.M., Cline, M.J. & Verma, I.M. Differential expression of cellular oncogenes during pre- and postnatal development of the mouse. Nature 299, 640–644 ( 1982).
Schwartzberg, P.L. et al. Mice homozygous for the ablm1 mutation show poor viability and depletion of selected B and T cell populations. Cell 65, 1165–1175 ( 1991).
Tybulewicz, V.L.J., Crawford, C.E., Jackson, P.K., Bronson, R.T. & Mulligan, R.C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153–1163 ( 1991).
Tondravi, M.M. et al. Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature 386, 81– 84 (1997).
Blair, H.C., Kahn, A.J., Crouch, E.C., Jeffrey, J.J. & Teitelbaum, S.L. Isolated osteoclasts resorb the organic and inorganic components of bone. J. Cell Biol. 102, 1164 –1172 (1986).
Owen, M. & Friedenstein, A.J. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found. Symp. 136, 42–60 (1988).
Stein, G.S., Lian, J.B. & Owen, T.A. Relationships of cell growth to the regulation of tissue specific gene expression during osteoblast differentiation. FASEB J. 4, 3111–3123 ( 1990).
Cook, H.C. Manual of Histological Demonstration Techniques (Butterworth, London, 1974).
Aubin, J.E., Liu, F., Malaval, L. & Gupta, A.K. Osteoblast and chondroblast differentiation. Bone 17, 77S –83S (1995).
Sawyers, C.L., McLaughlin, J., Goga, A., Havlik, M. & Witte, O.N. The nuclear tyrosine kinase c-Abl negatively regulates cell growth. Cell 77, 121– 131 (1994).
Wen, S.T., Jackson, P.K. & Van Etten, R.A. The cytostatic function of c-Abl is controlled by multiple nuclear localization signals and requires the p53 and Rb tumor suppressor gene products. EMBO J. 15, 1583– 1595 (1996).
Quarles, L.D., Yohay, D.A., Lever, L.W., Caton, R. & Wenstrup, R.J. Distinct proliferative and differentiated stages of murine MC3T3-E1 cells in culture: an in vitro model of osteoblast development . J. Bone Miner. Res. 7, 683– 692 (1992).
Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45– 51 (1997).
Ducy, P., Zhang, R., Geoffroy, V., Ridall, A.L. & Karsenty, G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89, 747– 754 (1997).
Mundlos, S. et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89, 773– 779 (1997).
Otto, F. et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765–771 ( 1997).
Moursi, A.M. et al. Fibronectin regulates calvarial osteoblast differentiation J. Cell Sci. 109, 1369– 1380 (1996).
Lewis, J.M., Baskaran, R., Taagepera, S., Schwartz, M.A. & Wang, J.Y. Integrin regulation of c-Abl tyrosine kinase activity and cytoplasmic-nuclear transport. Proc. Natl Acad. Sci. USA 93, 15174–15179 (1996).
Hardin, J.D. et al. Bone marrow B lymphocyte development in c-abl deficient mice . Cell. Immunol. 165, 44– 54 (1995).
Takahashi, N. et al. Induction of calcitonin receptors by 1 a, 25-dihydroxyvitamin D3 in osteoclast-like multinucleated cells formed from mouse bone marrow cells . Endocrinology 123, 1504– 1510 (1988).
Engleman, V.W. et al. A peptidomimetic antagonist of the α(v)β3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo. J. Clin. Invest. 99, 2284–2292 (1997).
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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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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