Ageing is associated with reduction of mechanically-induced activation of Smad2/3P signaling in articular cartilage

Madej, Wojciech; Caam, A. van; Davidson, E.N. Blaney; Hannink, Gerjon; Buma, P.; Kraan, P.M. van der

doi:10.1016/j.joca.2015.07.018

Cited by 48 publications

(52 citation statements)

References 34 publications

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“…As TGFb is one of the growth factors present in the pericellular matrix and decreases in cartilage with age (Madej et al . ; van Caam et al . ), it is tempting to speculate that its release upon tissue compression could be relevant to reduced mechanoadaptation over the life course, a process described in other skeletal tissues (Greig et al .…”

Section: Articular Cartilage Is Adapted To Withstand Mechanical Stressmentioning

confidence: 95%

Mechanoadaptation: articular cartilage through thick and thin

Vincent

Wann

2018

The Journal of Physiology

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The articular cartilage is exquisitely sensitive to mechanical load. Its structure is largely defined by the mechanical environment and destruction in osteoarthritis is the pathophysiological consequence of abnormal mechanics. It is often overlooked that disuse of joints causes profound loss of volume in the articular cartilage, a clinical observation first described in polio patients and stroke victims. Through the 1980s, the results of studies exploiting experimental joint immobilisation supported this. Importantly, this substantial body of work was also the first to describe metabolic changes that resulted in decreased synthesis of matrix molecules, especially sulfated proteoglycans. The molecular mechanisms that underlie disuse atrophy are poorly understood despite the identification of multiple mechanosensing mechanisms in cartilage. Moreover, there has been a tendency to equate cartilage loss with osteoarthritic degeneration. Here, we review the historic literature and clarify the structural, metabolic and clinical features that clearly distinguish cartilage loss due to disuse atrophy and those due to osteoarthritis. We speculate on the molecular sensing pathways in cartilage that may be responsible for cartilage mechanoadaptation.

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Section: Articular Cartilage Is Adapted To Withstand Mechanical Stressmentioning

confidence: 95%

Mechanoadaptation: articular cartilage through thick and thin

Vincent

Wann

2018

The Journal of Physiology

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“…106). In a 2016 study of bovine cartilage explants subjected to , tissues from aged animals had deficient phosphorylation of SMAD2 and SMAD3 in response to loading compared with explants from young animals 105 . The exact mechanism responsible for this effect is difficult to deduce because, compared with young explants subjected to the same load, aged tissue showed less deformation, exhibited less upregulation of growth factors and also had lower levels of TGFR-1 on the cell surface.…”

Section: Changes In the Extracellular Matrixmentioning

confidence: 99%

“…Mechanical compression of bovine cartilage stimulates increased expression of the gene encoding transforming growth factor-β (TGF-β) and the subsequent phosphorylation of SMAD2 and SMAD3 through TGFR-1 (TGF-β receptor type-1), which increases matrix synthesis and limits catabolic signalling 105 . However, ageing causes a significant loss in expression of TGFR-1, resulting in a shift that favours TGF-β signalling through serine/threonine-protein kinase receptor R3 (SKR3, also known as TGF-β superfamily receptor type I).…”

Section: Changes In the Extracellular Matrixmentioning

confidence: 99%

Ageing and the pathogenesis of osteoarthritis

Loeser¹,

Collins²,

2016

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Ageing-associated changes that affect articular tissues promote the development of osteoarthritis (OA). Although ageing and OA are closely linked, they are independent processes. Several potential mechanisms by which ageing contributes to OA have been elucidated. This Review focuses on the contributions of the following factors: age-related inflammation (also referred to as ‘inflammaging’); cellular senescence (including the senescence-associated secretory phenotype (SASP)); mitochondrial dysfunction and oxidative stress; dysfunction in energy metabolism due to reduced activity of 5′-AMP-activated protein kinase (AMPK), which is associated with reduced autophagy; and alterations in cell signalling due to age-related changes in the extracellular matrix. These various processes contribute to the development of OA by promoting a proinflammatory, catabolic state accompanied by increased susceptibility to cell death that together lead to increased joint tissue destruction and defective repair of damaged matrix. The majority of studies to date have focused on articular cartilage, and it will be important to determine whether similar mechanisms occur in other joint tissues. Improved understanding of ageing-related mechanisms that promote OA could lead to the discovery of new targets for therapies that aim to slow or stop the progression of this chronic and disabling condition.

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“…With age, chondrocytes express higher levels of Alk1 [73]. Furthermore, Smad2/3 phosphorylation is induced by mechanical loading in young cartilage, but this mechanosensitive activation of Smad2/3 is impaired in aged cartilage [74]. As cartilage degrades and the biochemical composition and structure of the ECM are altered, the material properties of cartilage, including its elastic modulus, also change [75].…”

Section: Tissue-level Roles Of Tgfβ In Skeletal Mechanobiologymentioning

confidence: 99%

Mechanobiology of TGFβ signaling in the skeleton

2016

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Physical and biochemical cues play fundamental roles in the skeleton at both the tissue and cellular levels. The precise coordination of these cues is essential for skeletal development and homeostasis, and disruption of this coordination can drive disease progression. The growth factor TGFβ is involved in both the regulation of and cellular response to the physical microenvironment. It is essential to summarize the current findings regarding the mechanisms by which skeletal cells integrate physical and biochemical cues so that we can identify and address remaining gaps that could ultimately improve skeletal health. In this review, we describe the role of TGFβ in mechanobiological signaling in bone and cartilage at the tissue and cellular levels. We provide detail on how static and dynamic physical cues at the macro-level are transmitted to the micro-level, ultimately leading to regulation at each level of the TGFβ pathway and to cell differentiation. The continued integration of engineering and biological approaches is needed to answer many remaining questions, such as the mechanisms by which cells generate a coordinated response to physical and biochemical cues. We propose one such mechanism, through which the combination of TGFβ and an optimal physical microenvironment leads to synergistic induction of downstream TGFβ signaling.

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Ageing is associated with reduction of mechanically-induced activation of Smad2/3P signaling in articular cartilage

Cited by 48 publications

References 34 publications

Mechanoadaptation: articular cartilage through thick and thin

Mechanoadaptation: articular cartilage through thick and thin

Ageing and the pathogenesis of osteoarthritis

Mechanobiology of TGFβ signaling in the skeleton

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