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  • Review Article
  • Published:

Ageing and the pathogenesis of osteoarthritis

Nature Reviews Rheumatology volume 12, pages 412–420 (2016)Cite this article

Subjects

Key Points

  • Ageing-associated changes promote the development of osteoarthritis (OA), but ageing and OA are independent processes

  • Several hallmarks of ageing could contribute to OA: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication

  • The increase in fat mass and related metabolic changes that occur with ageing can result in ageing-related inflammation (referred to as 'inflammaging'), a chronic low-grade systemic proinflammatory state

  • Elevated levels of reactive oxygen species can contribute to OA by causing oxidative damage and disrupting normal cell signalling, leading to imbalanced anabolic and catabolic activity and ultimately cell death

  • Chondrocytes can undergo cellular senescence with age and OA in response to growth signals released as a result of underlying cellular damage

  • The non-enzymatic crosslinking of collagen that occurs with ageing alters the mechanical properties of cartilage, and the resulting changes to mechanotransduction pathways reduce extracellular matrix synthesis by chondrocytes

Abstract

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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Figure 1: Chondrocytes exhibit features of cellular senescence in the contexts of ageing and osteoarthritis.
Figure 2: Mitochondrial dysfunction, oxidative stress and changes in normal cell signalling in ageing and osteoarthritis.

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Acknowledgements

The authors' research work is funded by grants from the National Institute on Aging (RO1 AG044034 to R.F.L. and F32 AG050399 to B.O.D.).

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  1. Division of Rheumatology, Thurston Arthritis Research Center, Allergy, and Immunology, 3300 Thurston Building, Campus Box 7280, University of North Carolina School of Medicine, Chapel Hill, 27599–7280, North Carolina, USA

    Richard F. Loeser & John A. Collins

  2. Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, 450 West Drive, Campus Box 7295, Chapel Hill, 27599–7295, North Carolina, USA

    Brian O. Diekman

Authors
  1. Richard F. Loeser
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  2. John A. Collins
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  3. Brian O. Diekman
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Contributions

All authors researched data for the article and contributed to discussion of content, writing the article, and reviewing and editing the manuscript before submission.

Corresponding author

Correspondence to Richard F. Loeser.

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The authors declare no competing financial interests.

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Glossary

Telomere attrition

The shortening and deterioration of the protective caps on the ends of chromosomes that is associated with ageing.

Proteostasis

A state of protein homeostasis in which properly folded proteins are stabilized and damaged proteins are degraded.

Cellular senescence

A phenotypic state that can emerge in response to in vitro or in vivo cellular stress. Senescent cells do not divide upon stimulation and often display an altered secretory profile along with increased lysosomal activity.

Stem cell exhaustion

The inability of stem cells to provide a sufficient number of differentiated cells to maintain normal tissue function. Premature stem cell exhaustion can occur under conditions of high demand for progenitors or when aberrant signalling interrupts the maintenance of quiescence.

Senescence-associated secretory phenotype

(SASP). A cellular phenotype that is characterized by the production of high levels of certain inflammatory cytokines and matrix metalloproteinases. The SASP represents a mechanism by which senescent cells may function in a non-autonomous fashion.

Advanced glycation end-products

(AGEs). A diverse set of molecules formed by non-enzymatic reaction of proteins with reducing sugars such as glucose and ribose.

Anabolic dynamic compression

A process by which physical compression of cells within a tissue promotes an anabolic response by the cells.

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Loeser, R., Collins, J. & Diekman, B. Ageing and the pathogenesis of osteoarthritis. Nat Rev Rheumatol 12, 412–420 (2016). https://doi.org/10.1038/nrrheum.2016.65

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