Biological effects and osteoarthritic disease‐modifying activity of small molecule CM‐01

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.

Effects of a phosphocitrate analogue on osteophyte, subchondral bone advance, and bone marrow lesions in Hartley guinea pigs

“…Meniscal calcification, consistent with previous findings, 31 , 32 increased with age in the Hartley guinea pigs (data not shown). As expected, CM-01, a powerful calcification inhibitor, 29 reduced meniscal calcification ( Fig. 1 ).…”

“…We have shown previously that intraperitoneal injection of PC or PC analogue inhibited cartilage degeneration in a Hartley guinea pig model of post-traumatic OA. 28 , 29 In this study, we show that orally administered CM-01 not only inhibited cartilage degeneration, but also inhibited meniscal calcification, subchondral bone advance, osteophyte formation, and BMLs. The reduction in articular cartilage degeneration was accompanied by a significant reduction in the level of MMP13 protein expression, a major collagen II-degrading enzyme within the articular cartilage.…”

“… 25 - 27 We recently demonstrated that intraperitoneal injection of PC and PC analogues inhibited cartilage degeneration in Hartley guinea pig models of post-traumatic OA. 28 , 29 However, the prospect of PC as an oral disease-modifying drug for human OA therapy might be limited because PC contains a phosphate-oxygen atom-carbon (P-O-C) bond and five negative charges. The P-O-C bond is vulnerable to degradation by alkaline phosphatases in vivo , and the five negative charges make PC less permeable to intestinal membrane.…”

Naturally Occurring Osteoarthritis Features and Treatments: Systematic Review on the Aged Guinea Pig Model

“…Several studies have evaluated DH guinea pigs fed with standard diets enriched with rapamycin (rapa) with or without metformin [45], ad libitum regular or calorie-restricted chow with or without high fat diet (HFD) [46], Oleuropein and/or Rutin with or without Curcumin [47], water with a phosphocitrate analogue CM-01 [48], and D glucosamine (D-GlcN) or chondroitin sulfate sodium (CS) [49].…”

“…CM-01 was administered until 6, 12, and 18 months of age, showing a great contribution to reducing meniscal calcification, osteophyte, surface lesions, PG or chondrocyte loss, cartilage degeneration, Mankin score, and cartilage MMP13, and in increasing CT and cartilage bars in SB [48].…”