Osteoarthritis (OA) is the most common musculoskeletal disorder characterized by cartilage degradation and joint inflammation. Currently the only effective treatment is surgical joint replacement. MicroRNAs (miRNA) are a class of non-coding RNAs regulating gene expression by sequence specific inhibition of target mRNA translation. Specific miRNAs has been shown to exhibit altered pattern of expression in RA synovium and in other rheumatic diseases but their role in OA pathogenesis is yet to be defined. In our preliminary studies we analyzed the global expression of miRNAs in human chondrocytes stimulated with IL-12 and discovered that miRNA mir-27b (mir-27b), with no known function, was downregulated several fold. In silico analysis identified a number of possible target mRNAs including the matrix metalloproteinase-13 (MMP-13) mRNA. We have previously shown that a standardized pomegranate extract (PE) exert cartilage and chondroprotective effects by inhibiting the expression of MMP-13 in human cartilage explants in vitro and the development of inflammatory arthritis in a mouse model in vivo. Of relevance to the studies proposed in this application is our finding that downregulation of mir-27b by IL-12 was blocked by PE. Our basic hypothesis is that """"""""PE suppresses the IL-12-induced cartilage catabolic effects in OA by inhibiting the downregulation of mir-27b and other selected microRNAs that target MMP-13 mRNA in human chondrocytes"""""""". A corollary of this hypothesis is that """"""""bioactive constituents of PE exert their cartilage/ chondroprotective effects by modulating the expression of specific miRNAs that negatively regulate the expression of MMP-13 in vivo"""""""". We propose the following specific aims:
Specific Aim - 1: We will identify other miRNAs that target MMP-13 mRNA in human chondrocytes and are differentially modulated by IL-12. Using a larger number of patient samples we will confirm the effect of IL-12 on the expression of mir-27b and other miRNAs identified above and determine whether PE prevents their modulation by IL-12 in human OA chondrocytes in vitro.
Specific Aim -2: To determine the impact of altered expression of mir-27b and of other miRNAs identified above on the expression MMP-13 in human OA chondrocytes stimulated with IL-12 in vitro.
Specific Aim -3: In a mouse model of OA we will develop the miRNA expression profile in the joints during disease induction and progression. We will also examine the effect of PE consumption on the expression of miR-27b and other miRNAs that target MMP-13 in mouse OA joints and correlate their expression profile with the disease progression. Knowledge gained from these studies may provide insight into developing novel and cost effective therapeutic approaches for the treatment/ prevention of OA.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
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Special Emphasis Panel (ZRG1)
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Williamson, John S
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Northeast Ohio Medical University
Anatomy/Cell Biology
Schools of Medicine
United States
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Khan, Nazir M; Haqqi, Tariq M (2018) Epigenetics in osteoarthritis: Potential of HDAC inhibitors as therapeutics. Pharmacol Res 128:73-79
Ansari, M Y; Khan, N M; Ahmad, I et al. (2018) Parkin clearance of dysfunctional mitochondria regulates ROS levels and increases survival of human chondrocytes. Osteoarthritis Cartilage 26:1087-1097
Makki, Mohammad Shahidul; Akhtar, Nahid; Haqqi, Tariq M (2017) An effective and efficient method of transfecting primary human chondrocytes in suspension. Anal Biochem 526:29-32
Akhtar, Nahid; Khan, Nazir M; Ashruf, Omer S et al. (2017) Inhibition of cartilage degradation and suppression of PGE2 and MMPs expression by pomegranate fruit extract in a model of posttraumatic osteoarthritis. Nutrition 33:1-13
Haseeb, Abdul; Ansari, Mohammad Yunus; Haqqi, Tariq M (2017) Harpagoside suppresses IL-6 expression in primary human osteoarthritis chondrocytes. J Orthop Res 35:311-320
Haseeb, Abdul; Khan, Nazir M; Ashruf, Omer S et al. (2017) A Polyphenol-rich Pomegranate Fruit Extract Suppresses NF-?B and IL-6 Expression by Blocking the Activation of IKK? and NIK in Primary Human Chondrocytes. Phytother Res 31:778-782
Khan, Nazir M; Haseeb, Abdul; Ansari, Mohammad Y et al. (2017) Wogonin, a plant derived small molecule, exerts potent anti-inflammatory and chondroprotective effects through the activation of ROS/ERK/Nrf2 signaling pathways in human Osteoarthritis chondrocytes. Free Radic Biol Med 106:288-301
Khan, Nazir M; Ansari, Mohammad Y; Haqqi, Tariq M (2017) Sucrose, But Not Glucose, Blocks IL1-?-Induced Inflammatory Response in Human Chondrocytes by Inducing Autophagy via AKT/mTOR Pathway. J Cell Biochem 118:629-639
Khan, Nazir M; Haseeb, Abdul; Ansari, Mohammad Y et al. (2017) A wogonin-rich-fraction of Scutellaria baicalensis root extract exerts chondroprotective effects by suppressing IL-1?-induced activation of AP-1 in human OA chondrocytes. Sci Rep 7:43789
Makki, Mohammad S; Haqqi, Tariq M (2017) Histone deacetylase inhibitor vorinostat (SAHA, MK0683) perturb miR-9-MCPIP1 axis to block IL-1?-induced IL-6 expression in human OA chondrocytes. Connect Tissue Res 58:64-75

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