Title |
Disease-modifying effects of phosphocitrate and phosphocitrate-β-ethyl ester on partial meniscectomy-induced osteoarthritis
|
---|---|
Published in |
BMC Musculoskeletal Disorders, September 2015
|
DOI | 10.1186/s12891-015-0724-x |
Pubmed ID | |
Authors |
Yubo Sun, Nikkole Haines, Andrea Roberts, Michael Ruffolo, David R. Mauerhan, Kim L. Mihalko, Jane Ingram, Michael Cox, Edward N. Hanley |
Abstract |
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. 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. 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. 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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 26 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Lecturer | 4 | 15% |
Researcher | 4 | 15% |
Student > Doctoral Student | 3 | 12% |
Student > Ph. D. Student | 3 | 12% |
Student > Bachelor | 2 | 8% |
Other | 5 | 19% |
Unknown | 5 | 19% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 11 | 42% |
Nursing and Health Professions | 2 | 8% |
Immunology and Microbiology | 2 | 8% |
Biochemistry, Genetics and Molecular Biology | 1 | 4% |
Agricultural and Biological Sciences | 1 | 4% |
Other | 2 | 8% |
Unknown | 7 | 27% |