Cartilage degradation biomarkers predict efficacy of a novel, highly selective matrix metalloproteinase 13 inhibitor in a dog model of osteoarthritis: confirmation by multivariate analysis that modulation of type II collagen and aggrecan degradation peptides parallels pathologic changes.
OBJECTIVE
To demonstrate that the novel highly selective matrix metalloproteinase 13 (MMP-13) inhibitor PF152 reduces joint lesions in adult dogs with osteoarthritis (OA) and decreases biomarkers of cartilage degradation.


METHODS
The potency and selectivity of PF152 were evaluated in vitro using 16 MMPs, TACE, and ADAMTS-4 and ADAMTS-5, as well as ex vivo in human cartilage explants. In vivo effects were evaluated at 3 concentrations in mature beagles with partial medial meniscectomy. Gross and histologic changes in the femorotibial joints were evaluated using various measures of cartilage degeneration. Biomarkers of cartilage turnover were examined in serum, urine, or synovial fluid. Results were analyzed individually and in combination using multivariate analysis.


RESULTS
The potent and selective MMP-13 inhibitor PF152 decreased human cartilage degradation ex vivo in a dose-dependent manner. PF152 treatment of dogs with OA reduced cartilage lesions and decreased biomarkers of type II collagen (type II collagen neoepitope) and aggrecan (peptides ending in ARGN or AGEG) degradation. The dose required for significant inhibition varied with the measure used, but multivariate analysis of 6 gross and histologic measures indicated that all doses differed significantly from vehicle but not from each other. Combined analysis of cartilage degradation markers showed similar results.


CONCLUSIONS
This highly selective MMP-13 inhibitor exhibits chondroprotective effects in mature animals. Biomarkers of cartilage degradation, when evaluated in combination, parallel the joint structural changes induced by the MMP-13 inhibitor. These data support the potential therapeutic value of selective MMP-13 inhibitors and the use of a set of appropriate biomarkers to predict efficacy in OA clinical trials.
Settle
Steven
S
Pfizer Global Research and Development, St. Louis, Missouri, USA.
Vickery
Lillian
L
Nemirovskiy
Olga
O
Vidmar
Tom
T
Bendele
Alison
A
Messing
Dean
D
Ruminski
Peter
P
Schnute
Mark
M
Sunyer
Teresa
T
D000818:Animals; D001169:Arthritis, Experimental; D015415:Biomarkers / Q000652:urine; D002358:Cartilage, Articular / Q000473:pathology / Q000503:physiopathology*; D024043:Collagen Type II / Q000652:urine; D004285:Dogs; D005260:Female; D053509:Matrix Metalloproteinase 13 / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D020370:Osteoarthritis, Knee / Q000473:pathology / Q000503:physiopathology*; D011743:Pyrimidines / Q000494:pharmacology*; D013582:Synovial Fluid / Q000737:chemistry; D013777:Tetrazoles / Q000494:pharmacology*
D015415:Biomarkers; D024043:Collagen Type II; D061965:Matrix Metalloproteinase Inhibitors; C553448:PF152 compound; D011743:Pyrimidines; D013777:Tetrazoles; D053509:Matrix Metalloproteinase 13