Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases

Troeberg L, Fushimi K, Khokha R, Emonard H, Ghosh P, Nagase H · FASEB Journal

Calcium PPS blocked the aggrecan-degrading activity of ADAMTS-4 and ADAMTS-5 at IC50 values of 10–40 nM by binding their non-catalytic domains, raised TIMP-3 in porcine cartilage about 3.5-fold by blocking its receptor-mediated endocytosis rather than by raising transcription, and increased TIMP-3's affinity for the aggrecanases more than 100-fold. Cartilage from TIMP-3-null mice was markedly less protected, so the protection runs through TIMP-3 rather than through direct enzyme inhibition.

Population

Recombinant aggrecanases, porcine and human osteoarthritic cartilage explants, and cartilage from TIMP-3-null mice

Intervention

Calcium PPS at graded nanomolar concentrations

Comparator

Untreated enzyme and explant controls

Limitations

Enzyme, explant and cell work only, with no animal or human dosing. The inhibition is substrate-dependent — potent against aggrecan, weak against a non-glycosylated recombinant substrate. Tested the calcium salt rather than the sodium salt used clinically, supplied by Arthropharm, with Ghosh (PPS's developer) among the authors; the grants named in the acknowledgements are Wellcome Trust and NIH.