title: 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.
authors.affiliation: Department of Experimental Medicine, University of L'Aquila, Via Vetoio - Coppito 2, L'Aquila 67100, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Peruzzi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cappariello
authors.forename: Andrea
authors.initials: A
authors.lastname: Del Fattore
authors.forename: Nadia
authors.initials: N
authors.lastname: Rucci
authors.forename: Fabrizio
authors.initials: F
authors.lastname: De Benedetti
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D002454:Cell Differentiation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D019061:src-Family Kinases
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D017077:Culture Media, Conditioned; D018975:Insulin-Like Growth Factor Binding Protein 5; D015850:Interleukin-6; C493716:Runx2 protein, mouse; D050796:STAT3 Transcription Factor; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human