Osteoarthritis (OA) is associated with past biomechanical injury to cartilage and with aging. However, biomechanical injury and aging do not inevitably lead to OA. This proposal will focus on chondrocyte-centered innate inflammatory mechanisms in OA. We have characterized cartilage catabolism- promoting effects on chondrocytes for inflammation-mediated release of the multifunctional protein transglutaminase 2 (TG2). TG2 is abundant in the OA cartilage extracellular matrix and TG2 transamidation catalytic activity increases in aging cartilage. We observed that TG2 is a biomarker of OA severity, and we validated that global TG2 knockout is protective for instability-induced knee OA in mice. To pinpoint biomechanical injury and stress induced cartilage innate inflammatory responses that provide a foundation upon which OA is then triggered or accelerated, we will examine the linkage of TG2 release and XBP1 (X-box binding protein 1) activation in chondrocyte innate inflammation, proposed by us as a central switching mechanism for OA development and progression. XBP1 activation is specific to activation of ER stress, and successful resolution of ER stress promotes cell recovery and survival from injury. However, XBP1 activation also plays a central role in multiple organ models of innate inflammation, including via Toll-like receptor activation. We observe that biomechanical injury induces activation of ER stress in chondrocytes. Moreover, we detect active XBP1 increased in human knee OA chondrocytes. We also observe that cultured TG2 deficient chondrocytes have decreased XBP1 activation, but that extracellular TG2 induces XBP1 activation. Furthermore, we have generated cartilage-specific XBP1 knockout mice to probe for XBP1 function in chondrocytes. Here, we will test a hypothetical model in which TG2 and XBP1, by transducing and/or amplifying responses to biomechanical injury and oxidative stress, switch on chondrocyte innate inflammatory stress to promote OA development and progression. We specifically aim to: 1. Test the hypothesis that TG2 increases biomechanical injury-induced and oxidative stress-related catabolic and apoptotic responses of cultured chondrocytes mediated by HIF-2alpha activation and TG2 guanine nucleotide binding. 2. Test the hypothesis that TG2 increases injury and oxidative stress-induced catabolic and apoptotic responses of cultured chondrocytes critically mediated by XBP1 activation and decreased AMPK activity. 3. Test the hypothesis, in complementary studies in mice, that both cartilage-specific TG2 and XBP1 deficiency are protective against development and progression of OA. Completion of these studies will shed new light on the pathogenesis of OA related to biomechanical injury and aging, and identify potential new therapeutic targets.

Public Health Relevance

to the VA Mission and Health Care in the USA: OA leads to intractable chronic pain, loss of mobility, decreased social independence, and physical incapacity, and enormous financial costs. Twelve percent of the overall burden of OA arises after joint trauma. Athletic capability is paramount for survival in military basic training and successful service. Individuals with a medical waiver for knee problems are 1.4 times more likely to be hospitalized for any diagnoses, and 8.0 times more likely to be militarily discharged. In the Armed Forces, 30% to 50% of disability cases are due to injury, and the leading conditions are degenerative lower back and knee conditions. A direct relationship exists for OA with prior joint trauma and aging in the VA and other health care systems, and in VISN22, for example, ~40% of veteran patients are 65 years of age or older, and most people over age 65 have OA. We urgently need new therapy targets for OA, since there are currently no disease-modifying drugs.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Immunology A (IMMA)
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VA San Diego Healthcare System
San Diego
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Chen, Liang-Yu; Lotz, Martin; Terkeltaub, Robert et al. (2018) Modulation of matrix metabolism by ATP-citrate lyase in articular chondrocytes. J Biol Chem 293:12259-12270
Abhishek, Abhishek; Neogi, Tuhina; Choi, Hyon et al. (2018) Review: Unmet Needs and the Path Forward in Joint Disease Associated With Calcium Pyrophosphate Crystal Deposition. Arthritis Rheumatol 70:1182-1191
Serrano, Ramon L; Chen, Liang-Yu; Lotz, Martin K et al. (2018) Impaired Proteasomal Function in Human Osteoarthritic Chondrocytes Can Contribute to Decreased Levels of SOX9 and Aggrecan. Arthritis Rheumatol 70:1030-1041
Bursill, David; Taylor, William J; Terkeltaub, Robert et al. (2018) Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) consensus statement regarding labels and definitions for disease elements in gout. Arthritis Care Res (Hoboken) :
Jin, Yunyun; Cong, Qian; Gvozdenovic-Jeremic, Jelena et al. (2018) Enpp1 inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling. Development 145:
Choi, Hyon; Neogi, Tuhina; Stamp, Lisa et al. (2018) New Perspectives in Rheumatology: Implications of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities Trial and the Associated Food and Drug Administration Public Safety Alert. Arthritis Rheumatol 70:1702-1709
McWherter, Charles; Choi, Yun-Jung; Serrano, Ramon L et al. (2018) Arhalofenate acid inhibits monosodium urate crystal-induced inflammatory responses through activation of AMP-activated protein kinase (AMPK) signaling. Arthritis Res Ther 20:204
Chen, L-Y; Wang, Y; Terkeltaub, R et al. (2018) Activation of AMPK-SIRT3 signaling is chondroprotective by preserving mitochondrial DNA integrity and function. Osteoarthritis Cartilage 26:1539-1550
Shadyab, A H; Terkeltaub, R; Kooperberg, C et al. (2018) Prospective associations of C-reactive protein (CRP) levels and CRP genetic risk scores with risk of total knee and hip replacement for osteoarthritis in a diverse cohort. Osteoarthritis Cartilage 26:1038-1044
Dalbeth, Nicola; Choi, Hyon K; Terkeltaub, Robert (2017) Review: Gout: A Roadmap to Approaches for Improving Global Outcomes. Arthritis Rheumatol 69:22-34

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