Hepatocyte growth factor/scatter factor modulates cell motility, proliferation, and proteoglycan synthesis of chondrocytes.

Abstract

Abstract. Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional growth factor that promotes proliferation, motility, and morphogenesis in epithelial cells. Recently the HGF receptor, c-met protooncogene product, has been shown to be expressed in developing limb buds (Sonnenberg, E., D. Meyer, M. Weidner, and C. Birchmeiyer. 1993. J. Cell Biol. 123: 223-235), suggesting that some populations of mesenchymal cells in limb buds respond to HGF/SF. To test the possibility that HGF/SF is involved in regulation of cartilage development, we isolated chondrocytes from knee joints and costal cartilages of 23-d embryonic and 4-wk-old rabbits, and analyzed the effects of HGF/SF on migration and proliferation of these cells. We found that HGF/SF stimulated migration of cultured articular chondrocytes but did not scatter limb mesenchymal fibroblasts or synovial fibroblasts in culture. HGF/SF also stimulated proliferation of chondrocytes; a maximum three-fold stimulation in DNA synthesis was observed at the concentration of 3 ng/ml of HGF/SF. Moreover, HGF/SF had the ability to enhance proteoglycan synthesis in chondrocytes. The responsiveness of chondrocytes to HGF/SF was also supported by the observation that they expressed the HGF/SF receptor. Addition of the neutralizing antibody to rat HGF/ SF affected neither DNA synthesis nor proteoglycan synthesis in rat chondrocytes, suggesting a paracine mechanism of action of HGF/SF on these cells. In situ hybridization analysis showed that HGF/SF mRNA was restrictively expressed in the areas of future joint regions in developing limb buds and in the intercostal spaces of developing costal cartilages. These findings suggest that HGF/SF plays important roles in cartilage development through its multiple activities.

Hepatocyte growth factor regulates the proliferation and differentiation of cartilage in developing forelimb of mouse embryos in vitro

“…Consistent with this, the organ culture study has demonstrated that exogenous HGF causes enhanced proliferation of chondrocytes, whereas antisense ODN and the specifi c antagonist of HGF cause impaired proliferation as well as enhanced hypertrophy and collagen X production of chondrocytes, evidence for cartilaginous differentiation. In articular and Meckel's cartilages, HGF is also known to stimulate proliferative activity as well as cell motility and matrix production of chondrocytes (50). The present in vivo and vitro results suggest that the intrinsic HGF produced by chondrocytes exerts an autocrine/paracrine function on chondrocytes in stimulating their proliferation while inhibiting their differentiation, resulting in prevention of endochondral ossifi cation in the anlagen of forelimb long bones.…”

“…In articular chondrogenesis, extrinsic HGF stimulates motility, proteoglycan synthesis, and proliferation of cultured articular chondrocytes, and intrinsic HGF mRNA is expressed in the mesenchymal areas of future joint regions in developing limb buds (50). However, the role of HGF in the development of the cartilage of bone anlagen and its endochondral ossifi cation has been unclear.…”

“…In addition to epithelial-mesenchymal interactions, HGF has been shown to play important roles in mesenchymal-mesenchymal interactions including the hematogenesis (21,49), angiogenesis (7,23), myogenesis in limb buds (13) and in tongue (3), chondrogenesis in articular cartilage (50) and in mandibular Meckel's cartilage (2). In articular chondrogenesis, extrinsic HGF stimulates motility, proteoglycan synthesis, and proliferation of cultured articular chondrocytes, and intrinsic HGF mRNA is expressed in the mesenchymal areas of future joint regions in developing limb buds (50).…”

Association between leukocyte telomere length and angiogenic cytokines in knee osteoarthritis

“…It has been demonstrated that HGF stimulated chondrocyte proliferation, motility and proteoglycan synthesis to facilitate repair mechanisms in response to cartilage damage. 22,23 Due to its osteogenic activity, HGF was also involved in bone-remodeling and osteophyte formation. 24 Vascular endothelial growth factor, a heparin-binding glycoprotein, is a member of the platelet-derived growth factor family.…”

“…29 HGF increases chondrocyte cell-division rates in vitro, expanding their total cell number. 22 VEGF can also promote endothelial cell proliferation to form new blood vessels. 25 Therefore, leukocytes, like the other cell types, are activated by high levels of these angiogenic cytokines in OA, and may proliferate with a higher rate.…”