Bone-derived growth factors modulate collagenase and TIMP (tissue inhibitor of metalloproteinases) activity and type I collagen degradation by mouse calvarial osteoblasts.
The finding that osteoblasts synthesize collagenase has led to the hypothesis that bone cells play a major role in bone resorption by degrading the surface osteoid layer, thereby preparing the underlying mineralized bone for osteoclastic action. To further understand the mechanisms regulating osteoid removal, mouse calvarial osteoblasts were cultured on 14C-labelled type I collagen films and the abilities of (i) bovine bone matrix extracts and (ii) purified or recombinant human growth factors, to modify their collagenolytic behaviour were investigated. EDTA/Tris-HCl extracts of bone matrix containing growth factor activity, exerted a dose-dependent inhibition of type I collagenolysis by osteoblasts stimulated with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, 10 ng/ml). Inhibition was accompanied by a reduction in collagenase activity and an increase in free TIMP (tissue inhibitor of metalloproteinases) in the culture medium. Transforming growth factor-beta, epidermal growth factor, platelet-derived growth factor and the acidic and basic fibroblast growth factors all mimicked these effects. In contrast, insulin-like growth factors-I and -II did not inhibit type I collagenolysis, only partially inhibited collagenase activity, and did not stimulate TIMP production by either 1,25(OH)2D3-treated or untreated cells. These findings provide additional evidence for the tight control exerted on the proteolytic activity of osteoblasts and the importance of TIMP in its regulation. They suggest strongly that the conversion (coupling) of the initial resorptive phase of the bone remodelling cycle to one of deposition, may be mediated by polypeptide growth factors either produced locally by osteoblasts, or released by proteolysis from the bone matrix.
Meikle
M C
MC
Cell Physiology Department, Strangeways Research Laboratory, Cambridge, England, U.K.
McGarrity
A M
AM
Thomson
B M
BM
Reynolds
J J
JJ
D000818:Animals; D000831:Animals, Newborn; D001857:Bone Matrix / Q000737:chemistry / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000032:analysis / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism*; D006133:Growth Substances / Q000032:analysis / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D003012:Microbial Collagenase / Q000378:metabolism*; D010006:Osteoblasts / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000494:pharmacology
D006023:Glycoproteins; D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D003094:Collagen; D003012:Microbial Collagenase; D002117:Calcitriol