OA is clearly associated with cartilage aging, but aging does not inevitably cause OA. Here, we aim to identify eariy aging-related chondrocyte abnormalities that provide a foundation upon which OA is then triggered or accelerated. Fundamental means by which cells normally resolve stress include proteostasis responses such as the unfolded protein response (UPR), which restores equilibrium to the stressed ER via a reprogrammed proteome, rich in chaperones and protein folding catalysts. The UPR also regulates oxidative stress responses, inflammation, and cell fate (normally promoting autophagy, but promofing apoptosis when damaged proteins exceed ER folding capacity). Three UPR signaling/proteolytic cascades are triggered by dissociation of distinct ER membrane proteins from the chaperone GRP78, each culminating in CHOP expression that successfully resolves the UPR, restoring normal protein synthesis and potentially promoting autophagy as opposed to apoptosis. Experimental UPR """"""""gain of function"""""""" and """"""""loss of function"""""""" have triggered cartilage pathology. Furthermore, UPR impairment is linked with aging and degenerative diseases in multiple tissues. We observe impaired CHOP expression in aging and OA cartilages. Moreover, GRP78, which dampens the UPR and inhibits apoptosis, is deficient in early OA, whereas, CHOP and GRP78 are induced by biomechanical stress in normal chondrocytes. Our central hypothesis is that impairment of the UPR due to deficient CHOP and GRP78 in articular chondrocytes are eariy changes of aging cartilage that renders cartilage more susceptible to OA development and progression. We specifically aim to: (1) Test the hypothesis that baseline impairment of the CHOP and GRP78 expression, particularly in the superficial zone, is a fundamental change of aging in articular cartilage and linked with autophagy;(2) Test the hypothesis that impaired CHOP and GRP78 responses to biomechanical and oxidative stress in aging cartilage promotes matrix loss, apoptosis, and decreased autophagy;and (3) Test the hypothesis, in complementary studies of mice, that CHOP deficiency promotes superficial zone chondrocyte dysfunction, matrix loss, and decreased autophagy in vitro, and aging and instability-induced OA in vivo.

Public Health Relevance

OA is a major public health probem in aging. The eariiest changes of aging that predispose to OA are not well understood. There is no adequate disease-modifying therapy for OA. This project has the potential to uncover eariy changes in aging cartilage to provide novel sites for intervention to prevent and slow the disease in aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG007996-21
Application #
8663764
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Wang, Yun; Viollet, Benoit; Terkeltaub, Robert et al. (2016) AMP-activated protein kinase suppresses urate crystal-induced inflammation and transduces colchicine effects in macrophages. Ann Rheum Dis 75:286-94
Nakamichi, Ryo; Ito, Yoshiaki; Inui, Masafumi et al. (2016) Mohawk promotes the maintenance and regeneration of the outer annulus fibrosus of intervertebral discs. Nat Commun 7:12503
Alvarez-Garcia, O; Olmer, M; Akagi, R et al. (2016) Suppression of REDD1 in osteoarthritis cartilage, a novel mechanism for dysregulated mTOR signaling and defective autophagy. Osteoarthritis Cartilage 24:1639-47
Grogan, Shawn P; Pauli, Chantal; Lotz, Martin K et al. (2016) Relevance of meniscal cell regional phenotype to tissue engineering. Connect Tissue Res :
Temple-Wong, Michele M; Ren, Shuwen; Quach, Phu et al. (2016) Hyaluronan concentration and size distribution in human knee synovial fluid: variations with age and cartilage degeneration. Arthritis Res Ther 18:18
Yadav, Manisha C; Bottini, Massimo; Cory, Esther et al. (2016) Skeletal Mineralization Deficits and Impaired Biogenesis and Function of Chondrocyte-Derived Matrix Vesicles in Phospho1(-/-) and Phospho1/Pi t1 Double-Knockout Mice. J Bone Miner Res 31:1275-86
Shen, T; Alvarez-Garcia, O; Li, Y et al. (2016) Suppression of Sestrins in aging and osteoarthritic cartilage: dysfunction of an important stress defense mechanism. Osteoarthritis Cartilage :
Goodrich, Laurie R; Chen, Albert C; Werpy, Natasha M et al. (2016) Addition of Mesenchymal Stem Cells to Autologous Platelet-Enhanced Fibrin Scaffolds in Chondral Defects: Does It Enhance Repair? J Bone Joint Surg Am 98:23-34
Meinert, Christoph; Schrobback, Karsten; Levett, Peter A et al. (2016) Tailoring hydrogel surface properties to modulate cellular response to shear loading. Acta Biomater :
Alvarez-Garcia, Oscar; Fisch, Kathleen M; Wineinger, Nathan E et al. (2016) Increased DNA Methylation and Reduced Expression of Transcription Factors in Human Osteoarthritis Cartilage. Arthritis Rheumatol 68:1876-86

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