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.
|Lata, Michal; Hettinghouse, Aubryanna S; Liu, Chuan-Ju (2018) Targeting tumor necrosis factor receptors in ankylosing spondylitis. Ann N Y Acad Sci :|
|Jian, Jinlong; Chen, Yuehong; Liberti, Rossella et al. (2018) Chitinase-3-like Protein 1: A Progranulin Downstream Molecule and Potential Biomarker for Gaucher Disease. EBioMedicine 28:251-260|
|Wei, Jian-Lu; Liu, Chuan-Ju (2018) Establishment of a Modified Collagen-Induced Arthritis Mouse Model to Investigate the Anti-inflammatory Activity of Progranulin in Inflammatory Arthritis. Methods Mol Biol 1806:305-313|
|Hettinghouse, Aubryanna; Liu, Ronghan; Liu, Chuan-Ju (2018) Multifunctional molecule ERp57: From cancer to neurodegenerative diseases. Pharmacol Ther 181:34-48|
|Chen, Yuehong; Jian, Jinlong; Hettinghouse, Aubryanna et al. (2018) Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease. J Mol Med (Berl) 96:1359-1373|
|Yi, Young-Su; Jian, Jinlong; Gonzalez-Gugel, Elena et al. (2018) p204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice. EBioMedicine 29:78-91|
|Wei, Jian-Lu; Fu, Wenyu; Hettinghouse, Aubryanna et al. (2018) Role of ADAMTS-12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor. Arthritis Rheumatol 70:1745-1756|
|Chen, Yuehong; Sud, Neetu; Hettinghouse, Aubryanna et al. (2018) Molecular regulations and therapeutic targets of Gaucher disease. Cytokine Growth Factor Rev 41:65-74|
|Jian, Jinlong; Li, Guangfei; Hettinghouse, Aubryanna et al. (2018) Progranulin: A key player in autoimmune diseases. Cytokine 101:48-55|
|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|
Showing the most recent 10 out of 41 publications