Oncostatin M Stimulates the Growth of Dermal Fibroblasts Via a Mitogen-Activated Protein Kinase-Dependent Pathway

Abstract

Oncostatin M (OSM), a member of the hemopoietic cytokine family, has been implicated in the process of fibrosis and dermal wound healing. As a part of an ongoing study of the mechanisms of fibrosis and dermal wound healing, we have investigated the mechanism of the growth regulation of dermal fibroblasts by OSM. OSM stimulates the mitogenesis of dermal fibroblasts in a dose-dependent manner. This effect was completely blocked by anti-OSM IgG, but not by anti-IL-6 IgG. Furthermore, OSM induction was abolished by genistein, a tyrosine kinase inhibitor, or by PD98059, a specific mitogen-activated protein (MAP) kinase pathway inhibitor, but not by calphostin C, a protein kinase C inhibitor. Immunoblotting analysis using a specific Ab against phosphorylated MAP kinase (Thr202/Tyr204) showed that OSM induces phosphorylation of MAP kinase in dermal fibroblasts. Furthermore, transient transfection of the dominant-negative mutant MAP kinase into dermal fibroblasts abolished the OSM induction. These results strongly suggest that OSM stimulates the growth of dermal fibroblasts via a MAP kinase-dependent pathway.

Oncostatin M stimulates proliferation, induces collagen production and inhibits apoptosis of human lung fibroblasts

“…The maximal e ect observed was at a concentration of 2 ng ml 71 . This mitogenic e ect is consistent with a recent study, which showed that OSM induced the proliferation of dermal ®broblasts (Ihn & Tamaki, 2000).…”

“…Incubation of ®broblasts with PD98059 markedly diminished OSM-induced mitogenesis, strongly suggesting that OSM stimulates the proliferation of ®bro-blasts via a MAPK-dependent pathway. Similar ®ndings have recently been reported for dermal ®broblasts (Ihn & Tamaki, 2000). Bornfeldt et al (1997) recently demonstrated that the MAPK pathway can either mediate or inhibit cell proliferation, depending on the induction of down-stream events, most notably COX-2 meditated production of PGE 2 .…”

“…Although OSM has been shown to inhibit the proliferation of cells derived from solid tumours as well as normal and malignant mammary epithelium (Liu et al, 1998), it is also a potent mitogen for dermal ®broblasts (Ihn & Tamaki, 2000), endothelial cells (Pourteau et al, 1999) and vascular smooth muscle cells (Grove et al, 1993). Furthermore, OSM stimulates extracellular matrix production in dermal ®broblasts, hepatic stellate cells and in the pancreas (Duncan et al, 1995, Ihn et al, 1997Bamber et al, 1998;Levy et al, 2000) suggesting that it may be involved in a variety of ®broproliferative diseases.…”

“…OSM has profound e ects on the behaviour of dermal ®broblasts (Ihn & Tamaki, 2000) as well as synovial and lung ®broblasts (Richards et al, 1997), suggesting that OSMR are present on ®broblasts. However, OSM has also been shown to induce cellular responses by engaging and activating the LIFR, which has also been demonstrated on human lung ®broblasts (Knight et al, 1999b;Mosley et al, 1996).…”

Monocyte‐dependent oncostatin M and TNF‐α synergize to stimulate unopposed matrix metalloproteinase‐1/3 secretion from human lung fibroblasts in tuberculosis

“…These are the first data specifically implicating MAP kinases in the regulation of OSM secretion, although OSM itself is known to induce MAP kinase phosphorylation in target cells [39,40]. The ERK inhibitor used is well validated, and does not affect other intracellular protein kinases at concentrations of <50 lM [41].…”