Matrix metalloproteinase-3 in articular cartilage is upregulated by joint immobilization and suppressed by passive joint motion.
Both underloading and overloading of joints can lead to articular cartilage degradation, a process mediated in part by matrix metalloproteinases (MMPs). Here we examine the effects of reduced loading of rat hindlimbs on articular cartilage expression of MMP-3, which not only digests matrix components but also activates other proteolytic enzymes. We show that hindlimb immobilization resulted in elevated MMP-3 mRNA expression at 6h that was sustained throughout the 21day immobilization period. MMP-3 upregulation was higher in the medial condyle than the lateral, and was greatest in the superficial cartilage zone, followed by middle and deep zones. These areas also showed decreases in safranin O staining, consistent with reduced cartilage proteoglycan content, as early as 7days after immobilization. One hour of daily moderate mechanical loading, applied as passive joint motion, reduced the MMP-3 and ADAMTS-5 increases that resulted from immobilization, and also prevented changes in safranin O staining. Intra-articular injections of an MMP-3 inhibitor, N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid (NNGH), dampened the catabolic effects of a 7day immobilization period, indicating a likely requirement for MMP-3 in the regulation of proteoglycan levels through ADAMTS-5. These results suggest that biomechanical forces have the potential to combat cartilage destruction and can be critical in developing effective therapeutic strategies.
Leong
Daniel J
DJ
Leni and Peter W. May Department of Orthopaedics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Gu
Xiang I
XI
Li
Yonghui
Y
Lee
Jonathan Y
JY
Laudier
Damien M
DM
Majeska
Robert J
RJ
Schaffler
Mitchell B
MB
Cardoso
Luis
L
Sun
Hui B
HB
D051722:ADAM Proteins / Q000235:genetics / Q000502:physiology; D000071116:ADAMTS5 Protein; D000818:Animals; D002358:Cartilage, Articular / Q000201:enzymology / Q000503:physiopathology* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006614:Hindlimb; D007150:Immunohistochemistry; D007596:Joints / Q000503:physiopathology*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D010619:Phenazines / Q000737:chemistry; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D010619:Phenazines; D012333:RNA, Messenger; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C518696:Adamts5 protein, rat; D019278:Matrix Metalloproteinase 3; C009195:safranine T