Disease-modifying effects of phosphocitrate and phosphocitrate-β-ethyl ester on partial meniscectomy-induced osteoarthritis

Yubo Sun, Nikkole Haines, Andrea Roberts, Michael Ruffolo, David R. Mauerhan, Kim L. Mihalko, Jane Ingram, Michael Cox, Edward N. Hanley

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Background: It is believed that phosphocitrate (PC) exerts its disease-modifying effects on osteoarthritis (OA) by inhibiting the formation of crystals. However, recent findings suggest that PC exerts its disease-modifying effect, at least in part, through a crystal-independent action. This study sought to examine the disease-modifying effects of PC and its analogue PC-β-ethyl ester (PC-E) on partial meniscectomy-induced OA and the structure-activity relationship. Methods: Calcification- and proliferation-inhibitory activities were examined in OA fibroblast-like synoviocytes (FLSs) culture. Disease-modifying effects were examined using Hartley Guinea pigs undergoing partial meniscectomy. Cartilage degeneration was examined with Indian ink, safranin-O, and picrosirius red. Levels of matrix metalloproteinase-13 (MMP-13), ADAM metallopeptidase with thrombospondin type 1 motif 5 (ADAMTS5), chemokine (C-C motif) ligand 5 (CCL5), and cyclooxygenase-2 (Cox-2) were examined with immunostaining. The effects of PC-E and PC on gene expressions in OA FLSs were examined with microarray. Results are expressed as mean ± standard deviation and analyzed using Student's t test or Wilcoxon rank sum test. Results: PC-E was slightly less powerful than PC as a calcification inhibitor but as powerful as PC in the inhibition of OA FLSs proliferation. PC significantly inhibited cartilage degeneration in the partial meniscectomied right knee. PC-E was less powerful than PC as a disease-modifying drug, especially in the inhibition of cartilage degeneration in the non-operated left knee. PC significantly reduced the levels of ADAMTS5, MMP-13 and CCL5, whereas PC-E reduced the levels of ADAMTS5 and CCL5. Microarray analyses revealed that PC-E failed to downregulate the expression of many PC-downregulated genes classified in angiogenesis and inflammatory response. Conclusions: PC is a disease-modifying drug for posttraumatic OA therapy. PC exerts its disease-modifying effect through two independent actions: inhibiting pathological calcification and modulating the expression of many genes implicated in OA. The β-carboxyl group of PC plays an important role in the inhibition of cartilage degeneration, little role in the inhibition of FLSs proliferation, and a moderate role in the inhibition of FLSs-mediated calcification.

Original languageEnglish (US)
Article number270
JournalBMC Musculoskeletal Disorders
Volume16
Issue number1
DOIs
StatePublished - Sep 30 2015

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Orthopedics and Sports Medicine

Fingerprint Dive into the research topics of 'Disease-modifying effects of phosphocitrate and phosphocitrate-β-ethyl ester on partial meniscectomy-induced osteoarthritis'. Together they form a unique fingerprint.

Cite this