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.
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.
|Meckes, J K; Caramés, B; Olmer, M et al. (2017) Compromised autophagy precedes meniscus degeneration and cartilage damage in mice. Osteoarthritis Cartilage 25:1880-1889|
|Hasei, Joe; Teramura, Takeshi; Takehara, Toshiyuki et al. (2017) TWIST1 induces MMP3 expression through up-regulating DNA hydroxymethylation and promotes catabolic responses in human chondrocytes. Sci Rep 7:42990|
|Mouser, Vivian H M; Levato, Riccardo; Bonassar, Lawrence J et al. (2017) Three-Dimensional Bioprinting and Its Potential in the Field of Articular Cartilage Regeneration. Cartilage 8:327-340|
|Shen, T; Alvarez-Garcia, O; Li, Y et al. (2017) Suppression of Sestrins in aging and osteoarthritic cartilage: dysfunction of an important stress defense mechanism. Osteoarthritis Cartilage 25:287-296|
|He, Sha; Johnson, Noah J J; Nguyen Huu, Viet Anh et al. (2017) Simultaneous Enhancement of Photoluminescence, MRI Relaxivity, and CT Contrast by Tuning the Interfacial Layer of Lanthanide Heteroepitaxial Nanoparticles. Nano Lett 17:4873-4880|
|Alvarez-Garcia, Oscar; Matsuzaki, Tokio; Olmer, Merissa et al. (2017) Age-related reduction in the expression of FOXO transcription factors and correlations with intervertebral disc degeneration. J Orthop Res 35:2682-2691|
|Akagi, R; Akatsu, Y; Fisch, K M et al. (2017) Dysregulated circadian rhythm pathway in human osteoarthritis: NR1D1 and BMAL1 suppression alters TGF-? signaling in chondrocytes. Osteoarthritis Cartilage 25:943-951|
|Hasegawa, Akihiko; Yonezawa, Tomo; Taniguchi, Noboru et al. (2017) Role of Fibulin 3 in Aging-Related Joint Changes and Osteoarthritis Pathogenesis in Human and Mouse Knee Cartilage. Arthritis Rheumatol 69:576-585|
|Asahara, Hiroshi; Inui, Masafumi; Lotz, Martin K (2017) Tendons and Ligaments: Connecting Developmental Biology to Musculoskeletal Disease Pathogenesis. J Bone Miner Res 32:1773-1782|
|Kalyanaraman, Hema; Ramdani, Ghania; Joshua, Jisha et al. (2017) A Novel, Direct NO Donor Regulates Osteoblast and Osteoclast Functions and Increases Bone Mass in Ovariectomized Mice. J Bone Miner Res 32:46-59|
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