Decreased C-Src Expression Enhances Osteoblast Differentiation and Bone Formation

Abstract

c-src deletion in mice leads to osteopetrosis as a result of reduced bone resorption due to an alteration of the osteoclast. We report that deletion/reduction of Src expression enhances osteoblast differentiation and bone formation, contributing to the increase in bone mass. Bone histomorphometry showed that bone formation was increased in Src null compared with wild-type mice. In vitro, alkaline phosphatase (ALP) activity and nodule mineralization were increased in primary calvarial cells and in SV40-immortalized osteoblasts from Src−/− relative to Src+/+ mice. Src-antisense oligodeoxynucleotides (AS-src) reduced Src levels by ∼60% and caused a similar increase in ALP activity and nodule mineralization in primary osteoblasts in vitro. Reduction in cell proliferation was observed in primary and immortalized Src−/− osteoblasts and in normal osteoblasts incubated with the AS-src. Semiquantitative reverse transcriptase-PCR revealed upregulation of ALP, Osf2/Cbfa1 transcription factor, PTH/PTHrP receptor, osteocalcin, and pro-alpha 2(I) collagen in Src-deficient osteoblasts. The expression of the bone matrix protein osteopontin remained unchanged. Based on these results, we conclude that the reduction of Src expression not only inhibits bone resorption, but also stimulates osteoblast differentiation and bone formation, suggesting that the osteogenic cells may contribute to the development of the osteopetrotic phenotype in Src-deficient mice.

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

“…2b), demonstrating the inverse correlation between this IL-6 upstream signal and osteoblast differentiation. Notably, this result was very similar to the well-known effect of c-Src downregulation on osteoblast differentiation 16 . In fact, we found comparable upregulation of these osteoblast-specific genes in osteoblasts treated with c-Src-siRNA (Fig.…”

“…This is a non-receptor tyrosine kinase, which belongs to a family of cytoplasmic tyrosine kinases (Protein Tyrosine Kinase family, PTKs), capable of communicating with a large number of different receptors 14,15 . c-Src activity maintains osteoblasts in a less differentiated status, negatively regulating the expression of differentiation markers 16 . Given the similarity of IL-6 and c-Src effects on osteoblasts, we hypothesized the existence of a functional loop between these two factors, which could provide new insights into the pathogenesis of inflammation-related and other bone diseases.…”

CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity

“…C-Src is largely involved in pathophysiology of osteoblasts (Marzia et al, 2000) and CD99 isoforms differently affect tumour metastasis K Scotlandi et al prostate cancer (Jee et al, 2003;Recchia et al, 2003) along with the significant role that it plays in the regulation of crucial processes implicated in the pathogenesis and progression of tumours, such as cell cycle, migration, resistance to anoikis and anchorage independence (Irby and Yeatman, 2000). Therefore, we evaluated its role as a possible mediator of CD99 functions.…”

How Cells Communicate in the Bone Remodelling Process

“…For example mice lacking c-fos, which are unable to generate osteoclasts [26], have reduced bone formation as well as resorption. In mice deficient in either c-src [13] or cathepsin K [14], however, bone resorption is inhibited without inhibition of the rate and extent of formation.…”

“…FosB-overexpressing transgenic mice bone formation is increased without any increase in resorption [12]. In mice deficient in either c-src [13] or the cathepsin K [14], …”