Administration of systemic matrix metalloproteinase inhibitors maintains bone mechanical integrity in adjuvant arthritis.
OBJECTIVE
To evaluate the influence of systemic tetracycline derived antimetalloproteinase compounds on bone morphology and mechanical integrity.


METHODS
Male Lewis rats (n = 78) were randomly assigned to one of 10 groups, comprising controls, adjuvant arthritis (AA), and adjuvant arthritis with various combinations of 2 chemically modified, non-antimicrobial tetracycline derivatives (CMT3 or CMT8) with either of 2 nonsteroidal antiinflammatory agents (flurbiprofen or tenidap). After AA induction (23 days), pharmacological efficacy was assessed by inflammatory indices, body mass changes, joint radiological destruction scores, and pyridinoline collagen derived crosslinks. The structural and material properties of the rat femoral neck were assessed biomechanically.


RESULTS
Neither CMT had an antiinflammatory effect, but flurbiprofen and tenidap (alone or together with either CMT) significantly reduced joint inflammation. Pyridinoline excretion increased markedly in untreated AA, but was substantially normalized by either CMT3 alone or by CMT8 with flurbiprofen. AA produced significant deleterious effects on femoral neck structure and mechanical properties. Administration of either CMT, however, had positive effects on the amount of bone and the biomechanical properties of rat femoral neck, but not the mineralization of the bone in the rat femoral neck.


CONCLUSIONS
These data suggest that tetracycline derived antimetalloproteinase compounds can significantly and positively influence bone mechanical integrity associated with inhibition of collagen breakdown.
Zernicke
R F
RF
McCaig Centre for Joint Injury and Arthritis Research, Department of Surgery, University of Calgary, Alberta, Canada.
Wohl
G R
GR
Greenwald
R A
RA
Moak
S A
SA
Leng
W
W
Golub
L M
LM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001835:Body Weight; D003432:Cross-Linking Reagents / Q000378:metabolism; D004195:Disease Models, Animal; D005272:Femur Neck / Q000187:drug effects / Q000502:physiology*; D005480:Flurbiprofen / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D000078183:Oxindoles; D051381:Rats; D011917:Rats, Inbred Lew; D013754:Tetracyclines / Q000494:pharmacology*; D016474:Weight-Bearing
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003432:Cross-Linking Reagents; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D000078183:Oxindoles; D013754:Tetracyclines; D005480:Flurbiprofen; C062866:tenidap; D008666:Metalloendopeptidases