Osteoarthritis (OA) is the most common musculoskeletal disease among the aging population in the United States and throughout the world. OA is characterized by degeneration of articular cartilage of the joints in hands, knees, spine and hips. While conditions predisposing to the development of OA have been identified the actual causes remain unknown. The current treatment options are limited to relief of symptoms using nonsteroidal anti-inflammatory drugs (NSAIDs). Due to complications associated with NSAIDs therapy, the use of herbal extracts for the treatment of OA is on the rise but most of these agents, sold as dietary supplements, have not been evaluated for their efficacy and safety. Pomegranate fruit (Punica granatum L) is revered through the ages for its medicinal properties. Pomegranate fruit or its extract (PFE) is widely used in several traditional medicinal systems for the treatment of inflammation and pain in arthritis and other diseases. Edible part of pomegranate fruit (PF) is rich in anthocyanins, a group of polyphenolic compounds that possess antioxidant and anti-inflammatory activities. Published work from this laboratory has shown that PFE exert a potent inhibitory effect on IL-1B-induced activation of p38-MAPK and JNK, NF-kB and expression of matrix metalloproteinases (MMPs) by human cartilage explants and chondrocytes in vitro. However, the mechanism of the inhibition of catabolic response remains elusive. Based on our published and preliminary studies we hypothesize that """"""""pomegranate fruit extract (PFE) inhibit the cartilage degrading effects of IL-1B by regulating the activation of signal transduction pathways and transcription factors which negatively or positively affect the IL-1B-induced transcription of genes associated with the catabolic or anabolic response in human chondrocytes"""""""". Proposed studies will determine whether PFE inhibit the MKK3 and MKK6 kinases(Specific Aim 1);inhibit the IL-1B-induced activation of NF-kB by modulating the activation of kinases upstream of IkB (inhibitor of NF-kB) including IKKa and IKKB (Specific Aim 2);whether PFE inhibit the IL-1B-induced oxidative stress and dedifferentiation of human chondrocytes (Specific Aims 3, 4);and determine whether """"""""consumption of PFE will inhibit the cartilage degradation and suppress the progression of experimentally induced OA in rabbits (Specific Aim 5). Our findings may open new avenues regarding the use of PFE or compounds derived from it for the treatment and/or prevention of OA.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT003627-06
Application #
8142731
Study Section
Special Emphasis Panel (ZRG1-MOSS-D (02))
Program Officer
Pontzer, Carol H
Project Start
2007-09-01
Project End
2012-11-30
Budget Start
2011-09-01
Budget End
2012-11-30
Support Year
6
Fiscal Year
2011
Total Cost
$198,789
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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
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
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, ?-Ketoglutarate (?-KG), and DNA hydroxymethylation levels by interleukin-1? in primary human chondrocytes. J Biol Chem 289:6877-85
Haseeb, Abdul; Haqqi, Tariq M (2013) Immunopathogenesis of osteoarthritis. Clin Immunol 146:185-96
Akhtar, Nahid; Haqqi, Tariq M (2012) MicroRNA-199a* regulates the expression of cyclooxygenase-2 in human chondrocytes. Ann Rheum Dis 71:1073-80
Rasheed, Zafar; Haqqi, Tariq M (2012) Endoplasmic reticulum stress induces the expression of COX-2 through activation of eIF2?, p38-MAPK and NF-?B in advanced glycation end products stimulated human chondrocytes. Biochim Biophys Acta 1823:2179-89
Akhtar, Nahid; Rasheed, Zafar; Ramamurthy, Sangeetha et al. (2010) MicroRNA-27b regulates the expression of matrix metalloproteinase 13 in human osteoarthritis chondrocytes. Arthritis Rheum 62:1361-71
Singh, Rashmi; Akhtar, Nahid; Haqqi, Tariq M (2010) Green tea polyphenol epigallocatechin-3-gallate: inflammation and arthritis. [corrected]. Life Sci 86:907-18
Rasheed, Zafar; Anbazhagan, Arivarasu N; Akhtar, Nahid et al. (2009) Green tea polyphenol epigallocatechin-3-gallate inhibits advanced glycation end product-induced expression of tumor necrosis factor-alpha and matrix metalloproteinase-13 in human chondrocytes. Arthritis Res Ther 11:R71

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