The long-term goal of this project is to determine the mechanisms by which signals generated through integrin receptors regulate chondrocyte function. The general overall hypothesis for these studies is that changes in the cartilage extracellular matrix (ECM), including production of ECM protein fragments, are recognized by chondrocyte integrins and initiate a cascade of events intended to remodel the ECM but which in arthritis result in further matrix destruction. The focus of this proposal is on signals generated through the a5b1 integrin which regulate production of catabolic mediators including cytokines and matrix metalloproteinases (MMPs). During the initial funding period, key signaling proteins were defined that must be activated in order for fibronectin fragment (FN-f) stimulation of the a5b1 integrin to result in increased MMP-13 production. Importantly, reactive oxygen species (ROS) were found to be necessary secondary messengers for this signaling pathway to be active. The overall goal of the competitive renewal will be to determine the mechanism of key redox regulated signaling events in the a5b1 integrin signaling pathway in articular chondrocytes. A unique aspect will be testing of the hypothesis that oxidation of specific cysteine residues to sulfenic acid is necessary for a5b1 integrin signaling that results in MMP-13 production. This important and recently discovered mechanism for regulation of cell signaling has not been reported in chondrocytes or elucidated in integrin signaling pathways. The following specific aims will be pursued: 1) Determine the redox sensitive mechanism of PYK2 activation after a5b1 integrin stimulation in articular chondrocytes;2) Determine the key redox sensitive signaling proteins downstream from PYK2 which are required for a5b1-mediated MMP-13 expression;and 3) Determine the role of the suppressor of cytokine signaling 3 (SOCS-3) in chondrocyte a5b1 integrin signaling. Public health relevance: The results from these studies will provide new and significant information needed to understand the basic molecular mechanisms which control processes in cartilage cells (chondrocytes) that are responsible for production of destructive enzymes that have been found to cause degradation and loss of cartilage tissue in people with arthritis. The successful completion of this work should provide novel targets for inhibiting cartilage destruction in arthritis and prevent or slow the development of arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049003-09
Application #
7878077
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2007-08-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
9
Fiscal Year
2010
Total Cost
$310,460
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Collins, John A; Diekman, Brian O; Loeser, Richard F (2018) Targeting aging for disease modification in osteoarthritis. Curr Opin Rheumatol 30:101-107
Wood, Scott T; Long, David L; Reisz, Julie A et al. (2016) Cysteine-Mediated Redox Regulation of Cell Signaling in Chondrocytes Stimulated With Fibronectin Fragments. Arthritis Rheumatol 68:117-26
Long, D L; Ulici, V; Chubinskaya, S et al. (2015) Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is increased in osteoarthritis and regulates chondrocyte catabolic and anabolic activities. Osteoarthritis Cartilage 23:1523-31
Hobbs, G Aaron; Mitchell, Lauren E; Arrington, Megan E et al. (2015) Redox regulation of Rac1 by thiol oxidation. Free Radic Biol Med 79:237-50
Yammani, Raghunatha R; Loeser, Richard F (2014) Brief report: stress-inducible nuclear protein 1 regulates matrix metalloproteinase 13 expression in human articular chondrocytes. Arthritis Rheumatol 66:1266-71
Loeser, Richard F; Goldring, Steven R; Scanzello, Carla R et al. (2012) Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum 64:1697-707
Lotz, Martin; Loeser, Richard F (2012) Effects of aging on articular cartilage homeostasis. Bone 51:241-8
Loeser, Richard F (2011) Aging and osteoarthritis. Curr Opin Rheumatol 23:492-6
Long, D L; Loeser, R F (2010) p38gamma mitogen-activated protein kinase suppresses chondrocyte production of MMP-13 in response to catabolic stimulation. Osteoarthritis Cartilage 18:1203-10
Beier, Frank; Loeser, Richard F (2010) Biology and pathology of Rho GTPase, PI-3 kinase-Akt, and MAP kinase signaling pathways in chondrocytes. J Cell Biochem 110:573-80

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