Basic fibroblast growth factor stimulates expression of interstitial collagenase and inhibitors of metalloproteinases in rat bone cells.
Basic fibroblast growth factor (bFGF) is a bone cell mitogen that affects osteoblastic function by suppressing type I collagen synthesis. The investigators in this study examined whether bFGF also regulates interstitial collagenase and tissue inhibitors of metalloproteinases (TIMPs) in osteoblast-enriched cells isolated from 22-day fetal rat calvariae. After exposure to 600 pM bFGF, interstitial collagenase messenger RNA (mRNA) levels, as determined by Northern hybridization analysis, increased after 2 h and were maximally stimulated to approximately 13-fold at 6 h. Exposure of osteoblast-enriched cells to 0.06-6 nM bFGF increased collagenase mRNA in a dose-dependent manner, and bFGF also increased immunoreactive collagenase measured in the culture medium by Western blot analysis. The protein synthesis inhibitor cycloheximide, as well as two inhibitors of protein kinase C, staurosporine and sangivamycin, prevented the bFGF induction of collagenase transcripts, whereas indomethacin, an inhibitor of prostaglandin synthesis, decreased the effect of bFGF on collagenase mRNA levels by about 50%. After exposure to 600 pM bFGF, levels of TIMP 1 and TIMP 3 mRNAs were also maximally stimulated to approximately 6-fold at 16 h and 4-fold at 6 h. bFGF did not modify TIMP 2 expression. In conclusion, bFGF may modulate degradation of collagenous bone matrix by inhibiting collagen as well as stimulating collagenase and TIMPs by osteoblasts.
Varghese
S
S
Department of Research, Saint Francis Hospital and Medical Center, Hartford Connecticut 06105, USA.
Ramsby
M L
ML
Jeffrey
J J
JJ
Canalis
E
E
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015152:Blotting, Northern; D002478:Cells, Cultured; D017364:Collagenases / Q000096:biosynthesis*; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D006023:Glycoproteins / Q000096:biosynthesis*; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D020781:Matrix Metalloproteinase 1; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011741:Pyrimidine Nucleosides / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases; D014158:Transcription, Genetic / Q000187:drug effects
D000470:Alkaloids; D000903:Antibiotics, Antineoplastic; D006023:Glycoproteins; D011741:Pyrimidine Nucleosides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D016222:Fibroblast Growth Factor 2; C005699:sangivamycin; D003513:Cycloheximide; D011493:Protein Kinase C; D017364:Collagenases; D020781:Matrix Metalloproteinase 1; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin