Expression of Phosphocitrate-Targeted Genes in Osteoarthritis Menisci

Sun, Yubo; Mauerhan, David R.; Steuerwald, Nury; Ingram, Jane A.; Kneisl, Jeffrey S.; Hanley, Edward N.

doi:10.1155/2014/210469

Cited by 7 publications

(7 citation statements)

References 49 publications

(41 reference statements)

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“…In previous studies, researchers discovered citrate could inhibit formation and growth of calcium crystals . On the other hand, researchers demonstrated that PC exerts its OA disease‐modifying effect, in part, by upregulating the expression of many genes classified in type II collagen and ossification, beside its effect of calcification inhibition . In the present study, we demonstrated that the serum citrate was associated with reduced knee cartilage defect score, indicating that serum citrate may have a protective effect against OA cartilage defects.…”

Section: Discussionsupporting

confidence: 55%

Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis

Bian

Ruan

et al. 2020

Int J of Rheum Dis

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Objective The aim of this study was to investigate cross‐sectional associations between serum levels of citrate and knee structural changes and cartilage enzymes in patients with knee osteoarthritis (OA). Method A total of 137 subjects with symptomatic knee OA (mean age 55.0 years, range 34‐74, 84% female) were included. Knee radiography was used to assess knee osteophytes, joint space narrowing (JSN) and radiographic OA assessed by Kellgren‐Lawrence (K‐L) grading system. T2‐weighted fat‐suppressed fast spin echo magnetic resonance imaging (MRI) was used to determine knee cartilage defects, bone marrow lesions (BMLs) and infrapatellar fat pad (IPFP) signal intensity alternations. Colorimetric fluorescence was used to measure the serum levels of citrate. Enzyme‐linked immunosorbent assay was used to measure the serum cartilage enzymes including matrix metalloproteinase (MMP)‐3 and MMP‐13. Results After adjustment for potential confounders (age, sex, body mass index), serum citrate was negatively associated with knee osteophytes at the femoral site, cartilage defects at medial femoral site, total cartilage defects, and total BMLs (odds ratio [OR] 0.17‐0.30, all P < .05). Meanwhile, serum citrate was negatively associated with IPFP signal intensity alteration (OR 0.30, P = .05) in multivariable analyses. Serum citrate was significantly and negatively associated with MMP‐13 (β −3106.37, P < .05) after adjustment for potential confounders. However, citrate was not significantly associated with MMP‐3 in patients with knee OA. Conclusion Serum citrate was negatively associated with knee structural changes including femoral osteophytes, cartilage defects, and BMLs and also serum MMP‐13 in patients with knee OA, suggesting that low serum citrate may be a potential indicator for advanced knee OA.

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Section: Discussionsupporting

confidence: 55%

Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis

Bian

Ruan

et al. 2020

Int J of Rheum Dis

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“…We recently demonstrated that PC inhibited the expression of numerous genes implicated in OA in the absence of calcium crystals in cell cultures and that PC inhibited cartilage degeneration in a Hartley guinea pig model of posttraumatic OA . These findings indicate that PC is not only a disease modifying drug for crystal‐associated primary OA therapy, but also a disease modifying drug for injury‐induced secondary posttraumatic OA therapy.…”

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confidence: 91%

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

Sun

Roberts

Mauerhan

et al. 2017

Journal Orthopaedic Research

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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.

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“…We recently found that PC downregulated the expression of many genes classified in cell proliferation, angiogenesis, and inflammatory response, while upregulating the expressions of many genes classified in skeletal system development in the absence of calcium crystals [ 29 – 31 ]. These newer findings suggest that crystal-dependent action of PC may not be a sole action underlying the OA disease-modifying effect of PC.…”

Section: Introductionmentioning

confidence: 99%

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

Sun

Haines

Roberts

et al. 2015

BMC Musculoskelet Disord

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BackgroundIt 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.MethodsCalcification- 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.ResultsPC-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.ConclusionsPC 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.

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Expression of Phosphocitrate-Targeted Genes in Osteoarthritis Menisci

Cited by 7 publications

References 49 publications

Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis

Associations of serum citrate levels with knee structural changes and cartilage enzymes in patients with knee osteoarthritis

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

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

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