Osteoarthritis (OA) is the most prevalent joint disease. Therapies for established and measures to prevent OA are not available. While aging is a major OA risk factor, mechanisms of joint and cartilage aging remain to be characterized. Our overall hypothesis proposes that cartilage aging is associated with failure of cellular homeostasis mechanisms, causing cell dysfunction and death. This initially affects the superficial zone and triggers the cartilage remodeling and degradation process characteristic of OA. The overall goal of this program is to begin with phenotype identification, proceed to elucidation of mechanisms and key cellular and molecular abnormalities in order to provide new directions for correction of aging-associated risk factors for OA and therapeutic interventions for established OA. In this proposal we focus on the identification of early changes in cellular and joint homeostasis mechanisms upon which OA is triggered or accelerated in response to biomechanical or biochemical stressors. This competing renewal continues to utilize human knee joints from donors across the adult age spectrum to establish phenotypic changes in articular cartilage and other joint tissues that are characteristic of normal joint aging and may predispose to OA development. Access to human tissues provides a unique opportunity to test the human and clinical relevance of novel basic and molecular mechanisms not only through correlative studies but also through an array of mechanistic studies with cells isolated from human tissues. These studies will be complemented with mutant mouse models. The proposed program will continue the existing cores (A: Administration;PI M. Lotz;B: Tissue Acquisition, Morphology, and Cell Culture;PI D. D'Lima). The following 3 projects are proposed: Project 1 'Autophagy in Aging and Osteoarthritis'(PI M. Lotz) will characterize patterns and consequences of defective and pharmacologically enhanced autophagy in joint aging and OA;Project 2 'The Chondrocyte Unfolded Protein Response (UPR) in Aging and Osteoarthritis'(PI R. Terkeltaub) addresses mechanisms and consequences of impaired UPR in regards to chondrocyte survival and hypertrophy;and Project 3 'Mechanobiology of Human Articular Cartilage Degeneration: Aging and Osteoarthritis'(PI R. Sah) will analyze biomechanical mechanisms of early and advanced cartilage degeneration and determine consequences for chondrocyte function and survival.

Public Health Relevance

Results from the proposed studies will add important new information on the earliest changes in joint aging focusing on decompensation of homeostasis mechanisms which may lead to cell death, abnormal cartilage cell activation and differentiation, ultimately resulting in cartilage destruction. This new insight into mechanisms of pathogenesis has the potential to lead to the discovery of new biomarkers and therapeutic targets. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATION CORE;Dr. Martin K. Lotz, Core Leader (CL) DESCRIPTION (provided by applicant): The central theme of this program is to study aging of the human knee joint and its relationship to osteoarthritis (OA). The Administrative Core will focus efforts of the cores and projects on this theme, advance hypotheses and research directions and ascertain scientific progress. The core will provide administrative support for the most efficient utilization of resources. The core will maintain access to different sources of knee joints and cartilage and monitor sample processing by the cores and analysis by the projects. Core A also serves as the central unit for data management and maintains the database for all knee specimens that are studied in the program.
The Specific Aims of the Administrative Core are:
Aim 1. Monitor scientific progress in the individual projects.
Aim 2. Promote interactions among the investigators in the program.
Aim 3. Support young scientists and development of new projects.
Aim 4. Provide access to knees and cartilage samples.
Aim 5. Maintain central database.
Aim 6. Perform statistical analysis.
Aim 7. Coordinate all fiscal activities of the program.
Aim 8. Ascertain responsible conduct of research.
Aim 9. Enforce safety measures for work with hazardous materials.
Aim 1 0. Distribute tissues and tissue extracts to outside investigators.

Public Health Relevance

Osteoarthritis represents the most prevalent joint disease for which disease-modifying therapies are not available. Aging is the major risk factor for the development of OA, and this project is focused on the discovery of biomarkers and therapeutic targets. A multidisciplinary approach is used to study aging and OA related changes in the human knee. This core serves the function to thematically focus and direct the program.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-9 (04))
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Williams, John
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Scripps Research Institute
La Jolla
United States
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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
Ishitobi, Hiroyuki; Sanada, Yohei; Kato, Yoshio et al. (2018) Carnosic acid attenuates cartilage degeneration through induction of heme oxygenase-1 in human articular chondrocytes. Eur J Pharmacol 830:1-8
Alvarez-Garcia, Oscar; Matsuzaki, Tokio; Olmer, Merissa et al. (2018) FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration. Aging Cell 17:e12800
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Kalyanaraman, Hema; Schwaerzer, Gerburg; Ramdani, Ghania et al. (2018) Protein Kinase G Activation Reverses Oxidative Stress and Restores Osteoblast Function and Bone Formation in Male Mice With Type 1 Diabetes. Diabetes 67:607-623
Lee, Kwang Il; Olmer, Merissa; Baek, Jihye et al. (2018) Platelet-derived growth factor-coated decellularized meniscus scaffold for integrative healing of meniscus tears. Acta Biomater 76:126-134
Su, Alvin W; Chen, Yunchan; Wailes, Dustin H et al. (2018) Impact insertion of osteochondral grafts: Interference fit and central graft reduction affect biomechanics and cartilage damage. J Orthop Res 36:377-386
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
Matsuzaki, Tokio; Alvarez-Garcia, Oscar; Mokuda, Sho et al. (2018) FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis. Sci Transl Med 10:
Su, Alvin W; Chen, Yunchan; Dong, Yao et al. (2018) Biomechanics of osteochondral impact with cushioning and graft Insertion: Cartilage damage is correlated with delivered energy. J Biomech 73:127-136

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