Osteoarthritis (OA) is a degenerative joint disease that affects more than 46 million people in the United States alone. Since mechanisms by which OA ensues are largely unknown, there are no therapeutic targets that effectively prevent and treat the disease. However, growth factors, cytokines and matrix-degrading enzymes are strongly implicated in initiating and aggravating OA lesions. Thus, a molecular understanding of interplays among these molecules will provide invaluable information toward the search for novel therapeutic targets for OA. Our genome-wide screen for novel, differentially expressed genes in OA led to the isolation of progranulin (PGRN) as a novel OA-associated growth factor. In subsequent global screen for the binding proteins of PGRN, we were surprised to find that PGRN bound to TNF Receptors (TNFR). PGRN directly binds to TNFR2 with an approximately 600-fold higher affinity than TNF?, and PGRN-activated target gene expressions in chondrocytes depend on TNFR2. In addition, PGRN blocks the binding of TNF? to TNFR and inhibits TNF?-induced ADAMTS cleavage of cartilage oligomeric matrix protein (COMP). Deletion of the PGRN gene exacerbates, whereas recombinant PGRN prevents the spontaneous development of polyarthritis in TNF transgenic mice. This proposal specifically focuses on the hypothesis that PGRN exerts its chondroprotective role in the pathogenesis of OA by interacting with TNFR.
The Specific Aims are: (1) what are the molecular mechanisms and signaling pathways by which PGRN regulates chondrocyte metabolism? We will define the effects of PGRN and TNF? on chondrocyte metabolism, their signaling pathways, target gene expressions and inter-plays in chondrocytes. We will determine the dependence of the PGRN function on TNFR in chondrocytes and characterize the PGRN/TNFR receptor complexes. Normal and arthritic human chondrocytes, as well as wild- type and PGRN-/- murine articular chondrocytes, will be used. (2) Does PGRN play an important role in the initiation and progression of OA, and what are the mechanisms of its action in OA? We will take advantage of both systematic and inducible PGRN knockout mice to generate surgically-induced OA models. We will also determine whether recombinant PGRN protects mice against OA challenge and whether PGRN ameliorates existing OA. We will determine which TNFR is important for mediating PGRN's protective role in OA. By applying insights from in vitro studies (proposed in Aim 1) to the analysis of early and late events in the mouse models, we will gain understanding of the molecular events underlying the initiation and progression of OA. Successful completion of the proposed research will not only benefit our understanding of the molecular mechanisms by which growth factor and cytokine act in concert in chondrocytes and in OA, but may also lead to the development of novel therapeutic intervention strategies for degenerative diseases, including OA.
The proposed studies will present a novel chondroprotective growth factor and provide a better understanding of growth factor and cytokine in chondrocytes and in the pathogenesis of OA. Identification of novel molecules and their derivatives relevant to chondrocytes is the basis for developing and optimizing the application of the novel therapeutic targets in cartilage disorders, including OA.
|Zhao, Yunpeng; Liu, Ben; Liu, Chuan-ju (2014) Establishment of a surgically-induced model in mice to investigate the protective role of progranulin in osteoarthritis. J Vis Exp :e50924|
|Wei, Fanhua; Zhang, Yuying; Jian, Jinlong et al. (2014) PGRN protects against colitis progression in mice in an IL-10 and TNFR2 dependent manner. Sci Rep 4:7023|
|Konopka, Jessica; Richbourgh, Brendon; Liu, Chuanju (2014) The role of PGRN in musculoskeletal development and disease. Front Biosci (Landmark Ed) 19:662-71|
|Wei, Fanhua; Zhang, Yuying; Zhao, Weiming et al. (2014) Progranulin facilitates conversion and function of regulatory T cells under inflammatory conditions. PLoS One 9:e112110|
|Tian, Qingyun; Zhao, Yunpeng; Mundra, Jyoti Joshi et al. (2014) Three TNFR-binding domains of PGRN act independently in inhibition of TNF-alpha binding and activity. Front Biosci (Landmark Ed) 19:1176-85|
|Wei, Jianlu; Richbourgh, Brendon; Jia, Tanghong et al. (2014) ADAMTS-12: a multifaced metalloproteinase in arthritis and inflammation. Mediators Inflamm 2014:649718|
|Tian, Qingyun; Zhao, Shuai; Liu, Chuanju (2014) A solid-phase assay for studying direct binding of progranulin to TNFR and progranulin antagonism of TNF/TNFR interactions. Methods Mol Biol 1155:163-72|
|Wei, Jianlu; Liu, Chuan-ju; Li, Zongdong (2014) ADAMTS-18: a metalloproteinase with multiple functions. Front Biosci (Landmark Ed) 19:1456-67|
|Jian, Jinlong; Zhao, Shuai; Tian, Qingyun et al. (2013) Progranulin directly binds to the CRD2 and CRD3 of TNFR extracellular domains. FEBS Lett 587:3428-36|
|Zhao, Yun-Peng; Tian, Qing-Yun; Liu, Chuan-Ju (2013) Progranulin deficiency exaggerates, whereas progranulin-derived Atsttrin attenuates, severity of dermatitis in mice. FEBS Lett 587:1805-10|
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