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

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 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.

Second-generation TKI dasatinib inhibits proliferation of mesenchymal stem cells and osteoblast differentiation in vitro

“…Signaling through c-Abl and ephB4 promotes osteoblast differentiation. [13][14][15] Thus, inhibition of these kinases by dasatinib would possibly lead to reduced osteoblast differentiation, in line with our observations presented here. In our experiments we used BMP-2 to promote differentiation, and c-Abl has been shown to contribute to BMP-stimulated osteoblast differentiation.…”

Reduction of apoptosis in Rb-deficient embryos via Abl knockout

“…The Abl þ /À mice are healthy and normal; hence, one allele of Abl is sufficient for the proper development of the mouse (Tybulewicz et al, 1991;Li et al, 2000). It thus appears that the gene dosage-dependent proapoptotic function of Abl, manifested in the Rb-null embryos, is dispensable for normal embryonic development.…”

“…However, reduced apoptosis did not result in prolonged survival in the Rb À/À Abl À/À embryos. The Abl À/À mice exhibit a variety of developmental defects leading to late embryonic or neonatal lethality (Tybulewicz et al, 1991;Li et al, 2000). The Abl protein is localized to the cytoplasm and the nucleus and undergoes nucleo-cytoplasmic shuttling (Wang, 2000;Woodring et al, 2003).…”

“…The Abl-null mice exhibit neonatal lethality with an array of developmental defects including lymphopenia and osteoporosis (Tybulewicz et al, 1991;Li et al, 2000). In this study, we combined the Abl-null allele with the Rb-null allele and found that the loss of Abl could rescue apoptosis in a subset of Rb-null tissues between embryonic days E11-E13.…”

Cancer treatment with kinase inhibitors: what have we learnt from imatinib?

“…In addition, some tyrosine kinase-dependent defects may become significant only in stressed conditions, such as inflammation and tissue repair (Van Etten, 1999). However, in knockout mice there is evidence of osteoporosis and defective osteoblast maturation (Li et al, 2000); defects in spermatogenesis (Guerif et al, 2002); abnormal lymphoid proliferation and differentiation, and abnormal melanin metabolism (Van Etten, 1999;Hou et al, 2000). This latter observation is significant in view of clinical reports of hypopigmentation in patients receiving imatinib (Saikia et al, 2002;Hasan et al, 2003).…”