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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR061484-02
Application #
8299027
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2011-09-01
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$474,890
Indirect Cost
$193,890
Name
New York University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Zhao, Yun-peng; Wei, Jian-lu; Tian, Qing-yun et al. (2016) Progranulin suppresses titanium particle induced inflammatory osteolysis by targeting TNFα signaling. Sci Rep 6:20909
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
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 Arti J Orthop Res 34:12-4
Jian, Jinlong; Tian, Qing-Yun; Hettinghouse, Aubryanna et al. (2016) Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease. EBioMedicine :
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
Jian, Jinlong; Li, Guangfei; Hettinghouse, Aubryanna et al. (2016) Progranulin: A key player in autoimmune diseases. Cytokine :
Uddin, S M Z; Richbourgh, B; Ding, Y et al. (2016) Chondro-protective effects of low intensity pulsed ultrasound. Osteoarthritis Cartilage 24:1989-1998
Zhang, Yuying; Wei, Fanhua; Liu, Chuan-Ju (2015) Overexpression of ADAMTS-7 leads to accelerated initiation and progression of collagen-induced arthritis in mice. Mol Cell Biochem 404:171-9
Zhao, Hua; Gonzalezgugel, Elena; Cheng, Lei et al. (2015) The roles of interferon-inducible p200 family members IFI16 and p204 in innate immune responses, cell differentiation and proliferation. Genes Dis 2:46-56
Zhao, Yun-Peng; Liu, Ben; Tian, Qing-Yun et al. (2015) Progranulin protects against osteoarthritis through interacting with TNF-α and β-Catenin signalling. Ann Rheum Dis 74:2244-53

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