Hepatocyte growth factor is involved in formation of osteoclast‐like cells mediated by clonal stromal cells (MC3T3‐G2/PA6)

Abstract

Osteoclast formation from hemopoietic precursors has been shown to require the support of stromal cells in bone tissue. In this study, we demonstrated that hepatocyte growth factor (HGF) is one of the stromal cell-derived molecules responsible for osteoclast-like cell formation. For our experiments, we used a coculture system for osteoclastic cell formation and activation in which hemopoietic blast cells are cocultured with calvaria-derived stromal MC3T3-G2/PA6 (PA6) cells on dentine slices in the presence of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Addition of anti-HGF neutralizing IgG to the cocultures inhibited the formation of osteoclastic cells and their dentine-resorbing activity. We detected a single 6.0-kb transcript for HGF in PA6 cells, and also recognized immunoreactive M(r) 81,000 and 88,000 forms of HGF in conditioned medium (CM) from PA6 cell cultures, the level of which reached 6 ng/ml. Both the CM and HGF stimulated the proliferation of blast cells synergistically with granulocyte-macrophage colony-stimulating factor, resulting in an increased number of osteoclast precursors that respond to 1,25(OH)2D3 that are tartrate-resistant acid phosphatase-positive multinucleate cells in stromal cell-free blast cell cultures in plastic wells. The effect of the CM was diminished by the addition of anti-HGF IgG. However, neither the CM nor HGF stimulated the formation of osteoclastic cells and pits on dentine slices in the absence of PA6 cells. These results suggest that although HGF cannot completely replace stromal cells, it is one of the paracrine mediators produced by stromal cells that act on proliferation of osteoclastic cell precursors.

A Selective c-Met Inhibitor Blocks an Autocrine Hepatocyte Growth Factor Growth Loop in ANBL-6 Cells and Prevents Migration and Adhesion of Myeloma Cells

“…HGF might also be of importance for bone destruction seen in most patients with multiple myeloma. Possible mechanism for this is direct stimulatory effect of HGF on bone-resorbing osteoclasts (39,40) or HGFinduced release of the potent osteoclast activator IL-11 from osteoblasts (28). In this paper, we show for the first time that a selective inhibitor of c-Met is able to completely block the aforementioned direct effects of HGF on myeloma cells, as well as induction of IL-11 release from an osteoblastic cell line.…”

Concomitant Expression of Hepatocyte Growth Factor/Scatter Factor and the Receptor c-MET in Human Myeloma Cell Lines

“…TGF␤ has been proposed as a factor which preserves the balance in bone remodeling by controlling that increased resorption is counteracted by both a rise in bone formation and a decrease in bone resorption (46). HGF was recently shown to promote formation of osteoclasts from hematopoietic precursor cells (47), to attract osteoclasts to sites of bone resorption (48), and, in co-culture with osteoblasts, to increase the level of resorption (47,48). However, whether HGF affects bone remodeling in multiple myeloma directly or as an opponent to TGF␤ remains to be tested.…”

Combined Administration of BMP-2 and HGF Facilitate Bone Regeneration through Angiogenic Mechanisms

“…HGF and its receptor, c-Met, are also expressed in both osteoblasts and osteoclasts 55,56) . HGF, in combination with vitamin D3, facilitates growth and differentiation of human mesenchymal stem cells into osteogenic cells 57) .…”