title: Proteolysis involving matrix metalloproteinase 13 (collagenase-3) is required for chondrocyte differentiation that is associated with matrix mineralization.
abstract: Collagenases are involved in cartilage matrix resorption. Using bovine fetal chondrocytes isolated from physeal cartilages and separated into a distinct prehypertrophic subpopulation, we show that in serum-free culture they elaborate an extracellular matrix and differentiate into hypertrophic chondrocytes. This is characterized by expression of type X collagen and the transcription factor Cbfal and increased incorporation of 45Ca2+ in the extracellular matrix, which is associated with matrix calcification. Collagenase activity, attributable only to matrix metalloproteinase (MMP) 13 (collagenase-3), is up-regulated on differentiation. A nontoxic carboxylate inhibitor of MMP-13 prevents this differentiation; it suppresses expression of type X collagen, Cbfal, and MMP-13 and inhibits increased calcium incorporation in addition to inhibiting degradation of type II collagen in the extracellular matrix. General synthesis of matrix proteins is unaffected. These results suggest that proteolysis involving MMP-13 is required for chondrocyte differentiation that occurs as part of growth plate development and which is associated with matrix mineralization.
authors.affiliation: Joint Diseases Laboratory, Shriners Hospitals for Children, Canadian Hospital, Montreal, Quebec.
authors.forename: C William
authors.initials: CW
authors.lastname: Wu
authors.forename: Elena V
authors.initials: EV
authors.lastname: Tchetina
authors.forename: Fackson
authors.initials: F
authors.lastname: Mwale
authors.forename: Karen
authors.initials: K
authors.lastname: Hasty
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pidoux
authors.forename: Agnes
authors.initials: A
authors.lastname: Reiner
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chen
authors.forename: Harold E
authors.initials: HE
authors.lastname: Van Wart
authors.forename: A Robin
authors.initials: AR
authors.lastname: Poole
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002264:Carboxylic Acids / Q000494:pharmacology; D002417:Cattle; D002454:Cell Differentiation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology*; D003001:Cloning, Molecular; D024043:Collagen Type II / Q000378:metabolism; D017364:Collagenases / Q000235:genetics* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000201:enzymology; D006132:Growth Plate / Q000166:cytology / Q000201:enzymology; D015576:Hyperostosis / Q000201:enzymology / Q000473:pathology; D007211:Indoles / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008903:Minerals / Q000378:metabolism; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism
chemical_list: D002264:Carboxylic Acids; D024043:Collagen Type II; D004791:Enzyme Inhibitors; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D008903:Minerals; D009363:Neoplasm Proteins; C406074:RS 102481; D014157:Transcription Factors; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1; D002118:Calcium