Osteoarthritis (OA) is the most prevalent joint disease. Although aging represents one of the most important risk factors for OA, mechanisms leading to the aging-related cartilage degeneration remain to be determined. In particular, early changes that predispose to cell death and matrix disruption are not well characterized. Autophagy plays a fundamental role in cellular homeostasis, prevents aging-related pathology and extends lifespan In model organisms. It is a major physiological mechanism that targets altered and dysfunctional cytosolic macromolecules, membranes and organelles for delivery to lysosomes for degradation and recycling of its constituents. In articular cartilage, a postmitotic tissue which is characterized by a very low rate of cell turnover this mechanism would appear to be essential to maintain normal cell function and survival. Our preliminary results indicate that autophagy is constitutively active and apparently protective process for the maintenance of homeostasis in normal cartilage. By contrast, cartilage aging and OA in humans and experimental models are associated with a reduction of key autophagy mediators ULK1, Beclini and LC3 in articular cartilage, and this was accompanied by an increase in chondrocyte apoptosis. Based on these findings we propose the hypothesis that 'Aging-related and joint injury-induced inhibition of autophagy compromises chondrocyte survival and biosynthetic capacity, leading to failure of tissue homeostasis and initiating OA pathogenesis.' The proposed aims will test three specific hypotheses: (1) Cartilage aging is associated with abnormal expression of autophagy regulators and autophagy flux in a site and zone specific pattern and this is linked to protein aggregate formation, cell death and altered gene expression;(2) Experimental or aging-related spontaneous inhibition of autophagy regulators in chondrocytes results in abnormal biosynthetic responses and cell death;and (3) Pharmacological enhancement of autophagy ameliorates surgically-induced and aging-related OA.
This project will open new perspectives on mechanisms of joint homeostasis in joint aging and OA pathogenesis. In addition to examining mechanisms that are activated in established OA we will address early changes in joint homeostasis that precede cell loss and matrix damage. Results from these studies have potential to discover new approaches to maintain joint health and new therapeutic targets for OA.
|Terkeltaub, Robert (2014) Apolipoprotein a-I at the interface of vascular inflammation and arthritis. Arterioscler Thromb Vasc Biol 34:474-6|
|Zhao, Xianling; Petursson, Freyr; Viollet, Benoit et al. (2014) Peroxisome proliferator-activated receptor ? coactivator 1? and FoxO3A mediate chondroprotection by AMP-activated protein kinase. Arthritis Rheumatol 66:3073-82|
|Alvarez-Garcia, Oscar; Rogers, Nicole H; Smith, Roy G et al. (2014) Palmitate has proapoptotic and proinflammatory effects on articular cartilage and synergizes with interleukin-1. Arthritis Rheumatol 66:1779-88|
|Kato, Tomohiro; Miyaki, Shigeru; Ishitobi, Hiroyuki et al. (2014) Exosomes from IL-1? stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes. Arthritis Res Ther 16:R163|
|Grogan, Shawn P; Chen, Xian; Sovani, Sujata et al. (2014) Influence of cartilage extracellular matrix molecules on cell phenotype and neocartilage formation. Tissue Eng Part A 20:264-74|
|Mologne, Timothy S; Cory, Esther; Hansen, Bradley C et al. (2014) Osteochondral allograft transplant to the medial femoral condyle using a medial or lateral femoral condyle allograft: is there a difference in graft sources? Am J Sports Med 42:2205-13|
|Onizuka, Naoko; Ito, Yoshiaki; Inagawa, Masayo et al. (2014) The Mohawk homeobox transcription factor regulates the differentiation of tendons and volar plates. J Orthop Sci 19:172-80|
|Novitskaya, Ekaterina; Zin, Carolyn; Chang, Neil et al. (2014) Creep of trabecular bone from the human proximal tibia. Mater Sci Eng C Mater Biol Appl 40:219-27|
|Shapiro, Irving M; Layfield, Robert; Lotz, Martin et al. (2014) Boning up on autophagy: the role of autophagy in skeletal biology. Autophagy 10:7-19|
|Olee, Tsaiwei; Grogan, Shawn P; Lotz, Martin K et al. (2014) Repair of cartilage defects in arthritic tissue with differentiated human embryonic stem cells. Tissue Eng Part A 20:683-92|
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