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.

Public Health Relevance

Osteoarthritis (OA) is characterized by high levels of IL-12, excessive production of ROS and articular cartilage degeneration in the affected joints. However, its etiology and precise pathogenetic mechanisms remain unclear. MicroRNAs (miRNA) are a class of non-coding RNAs regulating gene expression by sequence-specific inhibition of target mRNA translation. Specific miRNAs have been shown to exhibit an altered pattern of expression in RA synovium and in other diseases. Currently there is limited information available on the expression of miRNAs in human chondrocytes but their role in OA is yet to be defined. In addition there is no information on the effects of dietary polyphenols on miRNA expression in any cell type. By studying the regulation of miRNA expression by bioavailable dietary constituents, our findings are likely to open the door for the development of novel therapeutic strategies for the treatment of OA and other diseases.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
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Special Emphasis Panel (ZRG1-MOSS-C (04))
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Williamson, John S
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Northeast Ohio Medical University
Anatomy/Cell Biology
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Sondag, Gregory R; Haqqi, Tariq M (2016) The Role of MicroRNAs and Their Targets in Osteoarthritis. Curr Rheumatol Rep 18:56
Khan, Nazir M; Ansari, Mohammad Y; Haqqi, Tariq M (2016) Sucrose, But Not Glucose, Blocks IL1-β-Induced Inflammatory Response in Human Chondrocytes by Inducing Autophagy via AKT/mTOR Pathway. J Cell Biochem :
Haseeb, Abdul; Ansari, Mohammad Yunus; Haqqi, Tariq M (2016) Harpagoside suppresses IL-6 expression in primary human osteoarthritis chondrocytes. J Orthop Res :
Ansari, Mohammad Y; Haqqi, Tariq M (2016) Interleukin-1β induced Stress Granules Sequester COX-2 mRNA and Regulates its Stability and Translation in Human OA Chondrocytes. Sci Rep 6:27611
Makki, Mohammad Shahidul; Haqqi, Tariq M (2015) miR-139 modulates MCPIP1/IL-6 expression and induces apoptosis in human OA chondrocytes. Exp Mol Med 47:e189
Akhtar, Nahid; Makki, Mohammad S; Haqqi, Tariq M (2015) MicroRNA-602 and microRNA-608 regulate sonic hedgehog expression via target sites in the coding region in human chondrocytes. Arthritis Rheumatol 67:423-34
Makki, Mohammad S; Haseeb, Abdul; Haqqi, Tariq M (2015) MicroRNA-9 promotion of interleukin-6 expression by inhibiting monocyte chemoattractant protein-induced protein 1 expression in interleukin-1β-stimulated human chondrocytes. Arthritis Rheumatol 67:2117-28
Bükülmez, Hülya; Khan, Fozia; Bartels, Cynthia F et al. (2014) Protective effects of C-type natriuretic peptide on linear growth and articular cartilage integrity in a mouse model of inflammatory arthritis. Arthritis Rheumatol 66:78-89
Haseeb, Abdul; Makki, Mohammad Shahidul; Haqqi, Tariq M (2014) Modulation of ten-eleven translocation 1 (TET1), Isocitrate Dehydrogenase (IDH) expression, α-Ketoglutarate (α-KG), and DNA hydroxymethylation levels by interleukin-1β in primary human chondrocytes. J Biol Chem 289:6877-85
Haseeb, Abdul; Chen, Dongxing; Haqqi, Tariq M (2013) Delphinidin inhibits IL-1β-induced activation of NF-κB by modulating the phosphorylation of IRAK-1(Ser376) in human articular chondrocytes. Rheumatology (Oxford) 52:998-1008

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