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

BMC Musculoskeletal Disorders

Edward N. Hanley²  Michael Cox²  Jane Ingram²  Kim L. Mihalko¹  David R. Mauerhan²  Michael Ruffolo²  Andrea Roberts²  Nikkole Haines²  Yubo Sun² 

[1] Department of Comparative Medicine, Carolinas Medical Center, Charlotte 28232, NC, USA;Department of Orthopedic Surgery, Carolinas Medical Center, Charlotte 28232, NC, USA

关键词: CCL-5;    ADAMTS5;    MMP-13;    Phosphocitrate;    Osteoarthritis;    Crystals;    Calcification;   

Others  :  1229511
DOI  :  10.1186/s12891-015-0724-x

 received in 2015-08-06, accepted in 2015-09-18,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Sun et al.

【 图 表 】

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