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

Abstract

Interleukin-6 (IL-6) and c-src impair osteoblast maturation in vitro and in vivo. Given the similar effects of these factors, they are likely to establish a functional loop to maintain osteoblasts in a less mature status. Here we describe a pathway whereby c-src stimulates IL-6 expression through the sTAT3 factor, which, in response to IL-6 induces insulin-like growth factor 5 (IGFBP5), a c-src activating factor that amplifies this loop only in immature osteoblasts. In contrast, in mature osteoblasts, IGFBP5 is enhanced by Runx2, but is no longer able to stimulate c-src activation, as this tyrosine kinase at this stage is downregulated. We find that the IGFBP5 produced by osteoblasts stimulates osteoclastogenesis and bone resorption, acting as an osteoblast-osteoclast coupling factor. Finally, we demonstrate that the integrated actions of c-src, IL-6 and IGFBP5 also have a role in vivo. We conclude that this pathway is relevant for bone metabolism, both in physiological and in pathological conditions.

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“…Interestingly, both CTGF and Igfbp5 have been independently found to inhibit osteoblast maturation and differentiation [63,64] while MGP is an ECM protein that has been shown to inhibit mineralization and apoptosis of chondrocytes [65]. These findings suggest that interactions between leukemia and the BM stroma induce changes towards an undifferentiated state of the tumor microenvironment that could contribute to disease progression and chemotherapy resistance [66].…”

The Crucial Role of c-Src Tyrosine Kinase in Bone Metabolism

“…Recently, we demonstrated that in osteoblasts c-Src regulates interleukin (IL)-6 and insulin-like growth factor binding protein (IGFBP)-5 expression (Peruzzi et al, 2012). More in details, c-Src controls IL-6 expression acting on STAT3, which is a downstream component of the IL-6 pathway and a transcription factor for IL-6 itself.…”

“…On the other hand, in mature osteoblasts c-Src is barely expressed and therefore this loop is inactive, although IGFBP5 is still expressed under the control of Runx2. In this context, IGFBP5 has been observed to enhance osteoclast formation and bone resorption, thus unveiling its new role in the coupling between osteoblast and osteoclast activities (Peruzzi et al, 2012).…”

<b>Histochemical assessment for osteoblastic activity coupled with dysfunctional osteoclasts in </b><i><b>c-src</b></i><b> deficient </b><b>mice </b>

“…Alternatively, local coupling factors linking bone resorption to subsequent formation have long been proposed as the key regulator of the bone remodeling process. TGFβ and IGF-1 (7,15,16) were postulated to function as a coupling factor, but during the decade, more candidates were raised-complement component 3a (24), matrix IGF-1 (6), E-secletin ligand 1 (40), integrated actions of c-Src, IL-6 and IGFBP5 (28), semaphorin 3A (14), and Dlx5 (29). Among these molecules, we postulated that EphB4/ephrinB2 (41) would behave as coupling factors as reported previously (21).…”