Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation.
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 fetus. Mice homozygous for mutations in the gene encoding c-Abl (AIM) display increased perinatal mortality, reduced fertility, foreshortened crania and defects in the maturation of B cells in bone marrow. 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.
Li
B
B
Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, New York, USA.
Boast
S
S
de los Santos
K
K
Schieren
I
I
Quiroz
M
M
Teitelbaum
S L
SL
Tondravi
M M
MM
Goff
S P
SP
D000469:Alkaline Phosphatase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015415:Biomarkers; D001842:Bone and Bones / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D016313:Genes, abl; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D008903:Minerals / Q000378:metabolism; D010006:Osteoblasts / Q000201:enzymology / Q000473:pathology*; D015675:Osteocalcin / Q000096:biosynthesis / Q000235:genetics; D010010:Osteoclasts / Q000473:pathology; D010024:Osteoporosis / Q000235:genetics* / Q000473:pathology; D016315:Proto-Oncogene Proteins c-abl / Q000172:deficiency / Q000502:physiology*
D015415:Biomarkers; D008903:Minerals; D015675:Osteocalcin; D016315:Proto-Oncogene Proteins c-abl; D000469:Alkaline Phosphatase