SIRT1 directly activates autophagy in human chondrocytes

© 2020, The Author(s). Osteoarthritis (OA) is the most common form of arthritis worldwide with no effective treatment. Ageing is the primary risk factor for OA. We sought to investigate if there is a distinct and functional convergence of ageing-related mechanisms SIRT1 and autophagy in chondrocytes. Our results show that, levels of SIRT1 are decreased in human normal aged and OA cartilage compared with young cartilage. Moreover, silencing SIRT1 in chondrocytes lead to decreased expression of chondrogenic markers but did not alter the expression of catabolic proteases. In contrast, activation of SIRT1 increased autophagy in chondrocytes by the deacetylation of lysine residues on crucial autophagy proteins (Beclin1, ATG5, ATG7, LC3). This activation was shown to be mTOR/ULK1 independent. Our results indicate that maintenance of autophagy in chondrocytes by SIRT1 is essential for preserving cartilage integrity throughout life and therefore is a target for drug intervention to protect against OA

Cellular ageing mechanisms in osteoarthritis.

Age is the strongest independent risk factor for the development of osteoarthritis (OA) and for many years this was assumed to be due to repetitive microtrauma of the joint surface over time, the so-called 'wear and tear' arthritis. As our understanding of OA pathogenesis has become more refined, it has changed our appreciation of the role of ageing on disease. Cartilage breakdown in disease is not a passive process but one involving induction and activation of specific matrix-degrading enzymes; chondrocytes are exquisitely sensitive to changes in the mechanical, inflammatory and metabolic environment of the joint; cartilage is continuously adapting to these changes by altering its matrix. Ageing influences all of these processes. In this review, we will discuss how ageing affects tissue structure, joint use and the cellular metabolism. We describe what is known about pathways implicated in ageing in other model systems and discuss the potential value of targeting these pathways in OA

Cellular ageing mechanisms in osteoarthritis.

Age is the strongest independent risk factor for the development of osteoarthritis (OA) and for many years this was assumed to be due to repetitive microtrauma of the joint surface over time, the so-called 'wear and tear' arthritis. As our understanding of OA pathogenesis has become more refined, it has changed our appreciation of the role of ageing on disease. Cartilage breakdown in disease is not a passive process but one involving induction and activation of specific matrix-degrading enzymes; chondrocytes are exquisitely sensitive to changes in the mechanical, inflammatory and metabolic environment of the joint; cartilage is continuously adapting to these changes by altering its matrix. Ageing influences all of these processes. In this review, we will discuss how ageing affects tissue structure, joint use and the cellular metabolism. We describe what is known about pathways implicated in ageing in other model systems and discuss the potential value of targeting these pathways in OA

Aging mechanisms in arthritic disease.

Arthritic disease is one of the most common age-related pathologies worldwide. The erosion of cartilaginous tissues from articular surfaces within the joint and the failure to efficiently repair and regenerate this region with age lead to debilitating joint destruction, severe pain, and a crippling loss of function. In addition to the accumulative damage brought about by years of mechanical forces acting upon this region of tissue, there are also defects in underlying biological mechanisms which predispose the older population to excessive joint erosion. This occurs as aberrations in normal chondrocyte biology lead to a reduction in crucial matrix proteins and inhibitory molecules, and elevated production of destructive enzymes. The end result is an accelerated loss of articular cartilage and increased erosion of the joint. As a significant global link exists between aging and the onset of arthritis, this review will consider whether factors known to affect lifespan may also play a role in arthritic disease

Nociceptive sensitizers are regulated in damaged joint tissues, including the articular cartilage, when osteoarthritic mice display pain behaviour

Objective: Pain is the most common symptom of osteoarthritis yet where it originates in the joint and how it is driven is unknown. Methods: 10 week old mice underwent sham surgery or surgical joint destabilization by either partial meniscectomy (PMNX) or by destabilizing the medial meniscus (DMM). Pain-related behavior, by a variety of methods (von Frey, cold plate sensitivity, analgesimeter, incapacitance testing, forced flexion) was assessed weekly. Once pain-related behavior was established, RNA was extracted from either whole joints or micro-dissected tissues (articular cartilage, meniscus, bone). RT-PCR was carried out for 54 genes known to regulate pain sensitization. Cartilage injury assays were performed using avulsed immature murine hips from wild type or genetically modified animals, or by explanting articular cartilage from porcine joints pre-injected with pharmacological inhibitors. NGF protein was measured by ELISA. Results: Mice developed pain-related behavior 8 weeks following PMNX or 12 weeks following DMM. Nerve growth factor, bradykinin receptors B1 and B2, tachykinin and its receptor, were significantly regulated in the joints of mice displaying pain-related behavior. There was little regulation of inflammatory cytokines, leukocyte activation markers or chemokines. When tissues were analysed separately, NGF was consistently regulated in the articular cartilage. The other pain sensitizers were also largely regulated in the articular cartilage although there were some differences between the two models. Nerve growth factor and tachykinin were strongly regulated by simple mechanical injury of cartilage in vitro in a TAK1, FGF2 and Src kinase dependent manner. Conclusion: Damaged joint tissues produce pro-algesic molecules including NGF in murine OA. This article is protected by copyright. All rights reserved

Nociceptive sensitizers are regulated in damaged joint tissues, including the articular cartilage, when osteoarthritic mice display pain behaviour

Objective: Pain is the most common symptom of osteoarthritis yet where it originates in the joint and how it is driven is unknown. Methods: 10 week old mice underwent sham surgery or surgical joint destabilization by either partial meniscectomy (PMNX) or by destabilizing the medial meniscus (DMM). Pain-related behavior, by a variety of methods (von Frey, cold plate sensitivity, analgesimeter, incapacitance testing, forced flexion) was assessed weekly. Once pain-related behavior was established, RNA was extracted from either whole joints or micro-dissected tissues (articular cartilage, meniscus, bone). RT-PCR was carried out for 54 genes known to regulate pain sensitization. Cartilage injury assays were performed using avulsed immature murine hips from wild type or genetically modified animals, or by explanting articular cartilage from porcine joints pre-injected with pharmacological inhibitors. NGF protein was measured by ELISA. Results: Mice developed pain-related behavior 8 weeks following PMNX or 12 weeks following DMM. Nerve growth factor, bradykinin receptors B1 and B2, tachykinin and its receptor, were significantly regulated in the joints of mice displaying pain-related behavior. There was little regulation of inflammatory cytokines, leukocyte activation markers or chemokines. When tissues were analysed separately, NGF was consistently regulated in the articular cartilage. The other pain sensitizers were also largely regulated in the articular cartilage although there were some differences between the two models. Nerve growth factor and tachykinin were strongly regulated by simple mechanical injury of cartilage in vitro in a TAK1, FGF2 and Src kinase dependent manner. Conclusion: Damaged joint tissues produce pro-algesic molecules including NGF in murine OA. This article is protected by copyright. All rights reserved