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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Tyree, Bernadette
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New York University
Schools of Medicine
New York
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Wei, Jian-Lu; Fu, Wenyu; Ding, Yuan-Jing et al. (2017) Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models. Arthritis Res Ther 19:280
Jian, Jinlong; Hettinghouse, Aubryanna; Liu, Chuan-Ju (2017) Progranulin acts as a shared chaperone and regulates multiple lysosomal enzymes. Genes Dis 4:125-126
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Wei, Jian-Lu; Buza 3rd, John; Liu, Chuan-Ju (2016) Does progranulin account for the opposite effects of etanercept and infliximab/adalimumab in osteoarthritis?: Comment on Olson et al.: ""Therapeutic Opportunities to Prevent Post-Traumatic Arthritis: Lessons From the Natural History of Arthritis After Art J Orthop Res 34:12-4
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Zhao, Yun-peng; Wei, Jian-lu; Tian, Qing-yun et al. (2016) Progranulin suppresses titanium particle induced inflammatory osteolysis by targeting TNF? signaling. Sci Rep 6:20909
Kong, Li; Zhao, Yun-Peng; Tian, Qing-Yun et al. (2016) Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone-related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor. FASEB J 30:2741-54
Mundra, Jyoti Joshi; Jian, Jinlong; Bhagat, Priyal et al. (2016) Progranulin inhibits expression and release of chemokines CXCL9 and CXCL10 in a TNFR1 dependent manner. Sci Rep 6:21115
Zhao, Yun-Peng; Liu, Ben; Tian, Qing-Yun et al. (2015) Progranulin protects against osteoarthritis through interacting with TNF-? and ?-Catenin signalling. Ann Rheum Dis 74:2244-2253

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