期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 17, 页码 -出版社
MDPI
DOI: 10.3390/ijms21175992
关键词
ADAMTS-5; aggrecan; cartilage; biomarkers
资金
- Danish Research Foundation [2015-004]
Osteoarthritis (OA) is associated with cartilage breakdown, brought about by ADAMTS-5 mediated aggrecan degradation followed by MMP-derived aggrecan and type II collagen degradation. We investigated a novel anti-ADAMTS-5 inhibiting Nanobody(R)(M6495) on cartilage turnover ex vivo. Bovine cartilage (BEX,n= 4), human osteoarthritic - (HEX,n= 8) and healthy-cartilage (hHEX,n= 1) explants and bovine synovium and cartilage were cultured up to 21 days in medium alone (w/o), with pro-inflammatory cytokines (oncostatin M (10 ng/mL) + TNF alpha (20 ng/mL) (O + T), IL-1 alpha (10 ng/mL) or oncostatin M (50 ng/mL) + IL-1 beta (10 ng/mL)) with or without M6495 (1000-0.46 nM). Cartilage turnover was assessed in conditioned medium by GAG (glycosaminoglycan) and biomarkers of ADAMTS-5 driven aggrecan degradation (huARGS and exAGNxI) and type II collagen degradation (C2M) and formation (PRO-C2). HuARGS, exAGNxI and GAG peaked within the first culture week in pro-inflammatory stimulated explants. C2M peaked from day 14 by O + T and day 21 in co-culture experiments. M6495 dose dependently decreased huARGS, exAGNxI and GAG after pro-inflammatory stimulation. In HEX C2M was dose-dependently reduced by M6495. M6495 showed no effect on PRO-C2. M6495 showed cartilage protective effects by dose-dependently inhibiting ADAMTS-5 mediated cartilage degradation and inhibiting overall cartilage deterioration in ex vivo cartilage cultures.
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