Osteoprotegerin differentially regulates protease expression in osteoclast cultures.
Cysteine proteases and matrix metalloproteinases (MMPs) are important factors in the degradation of organic matrix components of bone. Osteoprotegerin (OPG) is an osteoblast-secreted decoy receptor that inhibits osteoclast differentiation and activation. This study investigated the direct effects of human OPG on cathepsin K, MMP-9, MMP-2, and tissue inhibitors of metalloproteinases (TIMP1 and TIMP2) expressed by purified rabbit osteoclasts. The expression of two osteoclast markers, namely tartrate-resistant acid phosphatase (TRAP) and cathepsin K, was inhibited by 100 ng/mL hOPG, whereas MMP-9 expression was enhanced. Gelatinase activities were measured using a zymographic assay, and hOPG was shown to enhance both pro-MMP-9 and MMP-2 activities. Concomitantly, TIMP1 expression was greatly stimulated by hOPG, whereas TIMP2 mRNA levels were not modulated. Overall, these results show that hOPG regulates the proteases produced by purified osteoclasts differentially, producing a marked inhibitory effect on the expression of cathepsin K, the main enzyme involved in bone resorption.
Wittrant
Y
Y
Faculté de Médecine, Laboratoire de Physiopathologie de la Résorption Osseuse, 1 rue Gaston Veil, 44035 Nantes cedex 01, France.
Couillaud
S
S
Theoleyre
S
S
Dunstan
C
C
Heymann
D
D
Rédini
F
F
D000135:Acid Phosphatase / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics; D002478:Cells, Cultured; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000235:genetics*; D010010:Osteoclasts / Q000201:enzymology*; D053244:Osteoprotegerin; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics
D017931:DNA Primers; D006023:Glycoproteins; D053244:Osteoprotegerin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C506030:TNFRSF11B protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D000135:Acid Phosphatase; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9