OBJECTIVE: To determine the effect of BAY 12-9566, a matrix metalloproteinase inhibitor, on articular cartilage metabolism in patients with osteoarthritis (OA). METHODS:Thirty-five patients with OA were randomized to receive oral daily dosing of BAY 12-9566 (25, 100, or 400 mg) or placebo for 3 weeks prior to knee surgery. Cartilage samples were obtained at surgery and examined for markers of proteoglycan aggrecan turnover (846 epitope, a putative synthesis marker, and keratan sulfate epitope content) and type II collagen synthesis (C-propeptide content), cleavage by collagenase (COL 2-3/4C short), denaturation, and content (COL2-3/4m epitope). BAY 12-9566 concentrations were measured by HPLC in serum, synovial fluid, and cartilage. RESULTS: Comparisons between study drug and placebo treatments revealed that at the 100 mg dose there was a significant increase in the 846 epitope (p = 0.012). Total type II collagen content was also higher at this dosage (p = 0.012). Alterations in collagen degradation and synthesis were not detected. CONCLUSION: BAY 12-9566 at daily doses of 100 mg significantly altered proteoglycan turnover, resulting in a cartilage composition reflected by the content of the 846 epitope that is more characteristic of a young growing individual. The increase in this epitope may signify increased matrix synthesis. The increase in type II collagen content was unexpected, since there was no other evidence for altered collagen turnover. However, increased matrix assembly would also be indicated by this increased content.
RCT Entities:
OBJECTIVE: To determine the effect of BAY 12-9566, a matrix metalloproteinase inhibitor, on articular cartilage metabolism in patients with osteoarthritis (OA). METHODS: Thirty-five patients with OA were randomized to receive oral daily dosing of BAY 12-9566 (25, 100, or 400 mg) or placebo for 3 weeks prior to knee surgery. Cartilage samples were obtained at surgery and examined for markers of proteoglycan aggrecan turnover (846 epitope, a putative synthesis marker, and keratan sulfate epitope content) and type II collagen synthesis (C-propeptide content), cleavage by collagenase (COL 2-3/4C short), denaturation, and content (COL2-3/4m epitope). BAY 12-9566 concentrations were measured by HPLC in serum, synovial fluid, and cartilage. RESULTS: Comparisons between study drug and placebo treatments revealed that at the 100 mg dose there was a significant increase in the 846 epitope (p = 0.012). Total type II collagen content was also higher at this dosage (p = 0.012). Alterations in collagen degradation and synthesis were not detected. CONCLUSION:BAY 12-9566 at daily doses of 100 mg significantly altered proteoglycan turnover, resulting in a cartilage composition reflected by the content of the 846 epitope that is more characteristic of a young growing individual. The increase in this epitope may signify increased matrix synthesis. The increase in type II collagen content was unexpected, since there was no other evidence for altered collagen turnover. However, increased matrix assembly would also be indicated by this increased content.
Authors: V B Kraus; B Burnett; J Coindreau; S Cottrell; D Eyre; M Gendreau; J Gardiner; P Garnero; J Hardin; Y Henrotin; D Heinegård; A Ko; L S Lohmander; G Matthews; J Menetski; R Moskowitz; S Persiani; A R Poole; J-C Rousseau; M Todman Journal: Osteoarthritis Cartilage Date: 2011-03-23 Impact factor: 6.576
Authors: Meagan J Makarczyk; Qi Gao; Yuchen He; Zhong Li; Michael S Gold; Mark C Hochberg; Bruce A Bunnell; Rocky S Tuan; Stuart B Goodman; Hang Lin Journal: Tissue Eng Part C Methods Date: 2021-02-04 Impact factor: 3.056