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

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.

• Authors: Yubo Sun, Nikkole Haines, Andrea Roberts, Michael Ruffolo, David R Mauerhan, Kim L Mihalko, Jane Ingram, Michael Cox, Edward N Hanley Jr
• Journal: BMC musculoskeletal disorders (BMC Musculoskelet Disord) Vol. 16 Pg. 270 (Sep 30 2015) ISSN: 1471-2474 [Electronic] England
• PMID: 26424660 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antirheumatic Agents
• Chemokine CCL5
• Citrates
• phosphocitrate
• Cyclooxygenase 2
• ADAM Proteins
• Matrix Metalloproteinase 13

Topics

• ADAM Proteins (genetics, metabolism)
• Animals
• Antirheumatic Agents (chemistry, pharmacology)
• Calcinosis (prevention & control)
• Cartilage, Articular (drug effects, metabolism, pathology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Chemokine CCL5 (genetics, metabolism)
• Citrates (chemistry, pharmacology)
• Cyclooxygenase 2 (genetics, metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Fibroblasts (drug effects, metabolism, pathology)
• Gene Expression Regulation
• Guinea Pigs
• Male
• Matrix Metalloproteinase 13 (genetics, metabolism)
• Menisci, Tibial (surgery)
• Molecular Structure
• Osteoarthritis (drug therapy, etiology, genetics, metabolism, pathology)
• Structure-Activity Relationship
• Synovial Membrane (drug effects, metabolism, pathology)