Macrophage-stimulating protein activates STK receptor tyrosine kinase on osteoclasts and facilitates bone resorption by osteoclast-like cells

Abstract

Recently we cloned a novel receptor tyrosine kinase, STK. STK belongs to the hepatocyte growth factor receptor family and was identified as the receptor for macrophage-stimulating protein (MSP). STK is expressed on a restricted, macrophage population such as peritoneal macrophages, but not on mononuclear phagocytes of peripheral blood, bone marrow, or alveoli. Using an anti-STK monoclonal antibody, we observed STK expression on multinuclear osteoclast-like cells (OCLs) formed by murine bone marrow cultures in the presence of 1,25-dihydroxyvitamin D3, and interleukin-3. The OCLs expressed both the calcitonin receptor and STK. We also detected STK expression in bone-derived mouse osteoclasts. The addition of MSP to OCLs induced rapid morphologic changes such as cytoplasmic contraction and formation of ruffled border. In addition, MSP caused rapid redistribution of src to the borders of cytoplasm. These phenomena were associated with enhanced bone resorption. MSP caused a threefold increase in pit formation compared with control OCLs. These findings suggest that by involving src kinase, the MSP/STK signal transduction pathway induces rapid cytoskeletal reorganization in osteoclasts and facilitates bone resorption by osteoclasts.

Receptor tyrosine kinases and the regulation of macrophage activation

“…STK/RON is not expressed on circulating monocytes, bone marrow-derived macrophages, splenic red pulp macrophages, or alveolar macrophages but is expressed on a number of specialized tissue macrophage populations ( Fig. 1B), including peritoneal macrophages, osteoclasts, mesangial cells, Kupffer cells, dermal macrophages, and marginal zone macrophages in the spleen [21][22][23] (and unpublished observations). Futhermore, LPS stimulation of macrophages in vitro or in vivo inhibits expression of STK [24]; however, the up-regulation of STK expression on day 3 concanavalin A-elicited peritoneal macrophages and at sites of wounding has been demonstrated [21,23].…”

Tyro 3 Receptor Tyrosine Kinase and its Ligand, Gas6, Stimulate the Function of Osteoclasts

“…Many receptor tyrosine kinases (RTK) phosphorylate themselves and other proteins in response to ligands. Macrophage-colony stimulating factor (M-CSF), M-CSF receptor (c-fms), macrophage-stimulating protein (MSP), and MSPreceptor (Ron/Stk) signal transduction systems play an important role in the development and function of osteoclasts [5][6][7].…”

STK/RON receptor tyrosine kinase mediates both apoptotic and growth signals via the multifunctional docking site conserved among the HGF receptor family.

“…MSP has multiple biological effects on murine resident peritoneal macrophages, such as the induction of chemotaxis and shape changes, the stimulation of ingestion (Skeel et al, 1991) and the inhibition of endotoxinor cytokine-induced expression of inducible nitric oxide synthase mRNA (M.-H. Wang et al, 1994b). Osteoclasts, a member of the mononuclear phagocyte system, were also found to express STK/RON, and MSP stimulates bone resorbing function through activation of src kinase (Kurihara et al, 1996). The STK/RON gene expression occurs relatively late in development in several organs, such as specific areas of the central and peripheral nervous systems, epithelia along the digestive tract, skin and lung (Gaudino et al, 1995;Quantin et al, 1995).…”