Inhibition of growth plate angiogenesis and endochondral ossification with diminished expression of MMP-13 in hypertrophic chondrocytes in FGF-2-treated rats.
Fibroblast growth factors (FGFs)/fibroblast growth factor receptor-3 signaling interferes with endochondral bone growth. However, the exact mechanisms by which FGFs inhibit endochondral ossification remain to be elucidated. In the present study, we utilized immunohistochemical techniques to clarify the effects of FGF-2 on the proximal tibial growth plate cartilage, when injected systemically into growing rats. In the FGF-2-treated rats, the growth plate was obviously thickened and, in the lowermost part, the hypertrophic chondrocytes were flattened, with an irregular arrangement. The connection of the cartilage columns and trabecular bone was disrupted. FGF-2 treatment stimulated the proliferation of chondrocytes and permitted their differentiation, but inhibited vascular invasion and resorption of the cartilage matrix. Expression of matrix metalloproteinase-13 (MMP-13) was detected in the chondrocytes in the last row of the hypertrophic zone of the growth plate in control animals. The immunoreactivity of MMP-13 was diminished in the regions where endochondral ossification was disturbed in the FGF-2-treated rats. Because MMP-13 has potent proteolytic activity on cartilage components, the FGF-2 signal may inhibit angiogenesis and endochondral ossification of the growth plate by the suppression of MMP-13 expression in hypertrophic chondrocytes.
Nagai
Hirofumi
H
Drug Safety Research Laboratories, Takeda Chemical Industries, 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
Aoki
Masami
M
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D024121:Collagen Type X / Q000032:analysis; D017364:Collagenases / Q000096:biosynthesis*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006132:Growth Plate / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013194:Staining and Labeling / Q000379:methods; D013977:Tibia / Q000378:metabolism
D024121:Collagen Type X; D061965:Matrix Metalloproteinase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D016222:Fibroblast Growth Factor 2; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat