Biological effects and osteoarthritic disease‐modifying activity of small molecule CM‐01. Issue 1 (13th June 2017)

• Record Type: Journal Article
• Authors: Sun, Yubo; Roberts, Andrea; Mauerhan, David R.; Cox, Michael; Hanley, Edward N.
• Is Part Of: Journal of orthopaedic research. Volume 36:Issue 1(2018)
• Page Start: 309
• Page End: 317
• Publication Date: 2017-06-13
• Subjects: calcification -- phosphocitrate -- osteoarthritis -- subchondral bone -- MMP‐13; Orthopedics -- Periodicals; Musculoskeletal system -- Periodicals; 616.7
• DOI: 10.1002/jor.23616
• Languages: English
• ISSNs: 0736-0266

Abstract

ABSTRACT: Phosphocitrate inhibits cartilage degeneration, however, the prospect of phosphocitrate as an oral disease modifying drug might be limited. The purpose of this study was to investigate the biological effects and disease‐modifying activity of a phosphocitrate "analog, " CM‐01 (Carolinas Molecule‐01), and test the hypothesis that CM‐01 is a disease modifying drug for osteoarthritis therapy. The effects of CM‐01 on calcium crystal‐induced expression of matrix metalloproteinase‐1 and interleukin‐1 beta, cell‐mediated calcification and production of proteoglycan by chondrocytes were examined in cell cultures. Disease‐modifying activity was examined using Hartley guinea pig model of posttraumatic osteoarthritis. Cartilage degeneration in untreated and CM‐01 treated guinea pigs was examined with Indian ink and Safranin‐O‐fast green. Levels of matrix metalloproteinase‐13, ADAM metallopeptidase with thrombospondin type 1 motif 5, chemokine (C‐C motif) ligand 5, and cyclooxygenase 2 were examined with immunostaining. CM‐01 inhibited crystal‐induced expression of matrix metalloproteinase‐1 and interleukin‐1β, reduced cell‐mediated calcification, and stimulated the production of proteoglycan by chondrocytes. In Hartley guinea pigs, CM‐01 not only reduced damages in articular surface but also reduced resorption of calcified zone cartilage. The reduction in cartilage degeneration was accompanied by decreased levels of matrix metalloproteinase‐13, ADAM metallopeptidase with thrombospondin type 1 motif 5, chemokine (C‐C motif) ligand 5 and cyclooxygenase 2. These findings confirmed that CM‐01 is a promising candidate to be tested as an oral drug for human OA therapy. CM‐01 exerted its disease‐modifying activity on osteoarthritis, in part, by inhibiting the production of matrix‐degrading enzymes and a molecular program resembling the endochondral pathway of ossification. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:309–317, 2018. Abstract : Biological effects and osteoarthritic disease‐modifying activity of small molecule CM‐01 Yubo Sun*, Andrea Roberts, David R Mauerhan, Michael Cox, and Edward N Hanley, Jr. This study investigated the biological and osteoarthritis (OA) disease‐modifying effects of a phosphocitrate "analog, " CM‐01. CM‐01 inhibited crystal‐induced expression of metalloproteinase‐1 and interleukin‐1β, calcification, and stimulated proteoglycan production. In Hartley guinea pigs, CM‐01 inhibited cartilage degeneration and the resorption of calcified zone cartilage. The reduction in cartilage degeneration was accompanied by decreased production of matrix‐degrading enzymes and inflammatory cytokines, demonstrating CM‐01 is a promising candidate to be tested as an oral drug for OA therapy.