Autophagy in osteoarthritis

doi:10.1016/j.jbspin.2015.06.009

Joint Bone Spine

Volume 83, Issue 2, March 2016, Pages 143-148

https://doi.org/10.1016/j.jbspin.2015.06.009 Get rights and content

Abstract

Degradation of the articular cartilage is at the centre of the pathogenesis of osteoarthritis (OA), for which age is the major risk factor. Maintaining the chondrocytes in a healthy condition appears to be an important factor for preservation of the entire cartilage and preventing its degeneration. Autophagy, which is an essential cellular homeostatic mechanism for the removal of dysfunctional cellular organelles and macromolecules, is increased by catabolic and nutritional stresses. Autophagy is increased in OA chondrocytes and cartilage, particularly during the initial degenerative phase, to regulate changes in OA-like gene expression through modulation of apoptosis and reactive oxygen species (ROS). In this way, autophagy acts as an adaptive response to protect chondrocytes from various environmental changes, while with gradual cartilage degradation, decreased autophagy is linked with cell death. Rapamycin, which is a specific inhibitor of the mTOR signaling pathway, enhances expression of autophagy regulators and prevents chondrocyte death. In the future, pharmacological activation of autophagy may be an effective therapeutic approach for OA.

Introduction

Osteoarthritis (OA), the most common age-related joint pathology, is a degenerative disease affecting all the structures of the joints and is characterized by articular cartilage destruction along with changes in other joint components, including bone, meniscus, synovium, ligament, capsule, and muscle [1]. Multiple factors have been implicated in the pathogenesis of OA, including mechanical, genetic, and age-associated factors, with age being the major risk factor for OA [2]. Chondrocytes are capable of responding to structural changes in the surrounding cartilage matrix although the capacity of adult articular chondrocytes to regenerate normal cartilage matrix architecture is limited and declines with age, due to cell death and abnormal responsiveness to anabolic stimuli [3]. Therefore, maintaining the chondrocytes in a healthy condition appears to be an important factor for preservation of the entire cartilage and preventing its degeneration. Autophagy (from auto-phagos: self-eating) is an essential cellular homeostatic mechanism for the removal of dysfunctional cellular organelles and macromolecules [4]. The autophagy pathway is integrated with multiple signal transduction pathways that respond to nutrient supply, energy balance, cytokines, and growth factors [4]. Here, we summarize the current understanding of the molecular mechanism of autophagy, focusing on recent studies that have examined the role of autophagy in the pathogenesis of OA.

Section snippets

Definition of autophagy

All living organisms undergo continuous renovation. Cells constantly adapt to changing environmental conditions by adjusting their content to prevailing needs. This process, known as homeostasis, involves continuous biosynthesis and turnover of cellular components. Eukaryotic cells have two major degradation systems: the lysosome and the proteasome [5]. Proteasomal degradation has high selectivity; the proteasome generally recognizes only ubiquitinated substrates, which are primarily

The basic process of autophagy

The main purpose of autophagy in yeast is to degrade the cytoplasm and recycle the resulting macromolecules for use in the synthesis of essential components during nutrient stress [14]. Although autophagy and autophagy-related processes are dynamic, they can be broken down into several discrete steps [14], [15]:

•
induction: in mammalian cells, autophagy occurs at a basal level under vegetative growth conditions. Accordingly, there must be a mechanism for sensing the extracellular milieu and

Regulatory factors

Several protein kinases and signaling pathways are involved in autophagy and autophagy-related processes. A number of critical autophagy-related genes (ATG or Atg) have been identified, the gene products of which regulate distinct steps in the induction or progression of autophagy [17]. The Ser/Thr protein kinase TOR, which plays a key role in signaling of nutrient limitation [18], resides in a multiprotein complex 1, mTORC1 [19]. In response to stimulation by nutrients or growth factors,

Expression of autophagy in OA

The articular cartilage is an avascular, aneural, alymphatic and viscoelastic connective tissue that derives its nutrition and oxygen supply by diffusion from the synovial fluid and the subchondral bone [32]. Chondrocytes are responsible for both synthesis and turnover of the abundant extracellular matrix (ECM) [3]; therefore, maintaining the chondrocytes in a healthy condition appears to be an important factor for maintaining the integrity of the entire cartilage. Autophagy has been suggested

Hypoxia, mechanical injury and autophagy

Articular cartilage is maintained in a low oxygen environment throughout life [32]. It has been demonstrated that an oxygen gradient exists in cartilage from around 6% at the joint surface to 1% in the deep layers [45]. Chondrocytes are therefore adapted to these hypoxic conditions. Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in the level of available oxygen in the cellular environment. Two main HIF isoforms (HIF-1α and HIF-2α) mediate the response of

Inflammation and autophagy

The inflammation of the synovial membrane that occurs in both the early and late phases of OA is associated with alterations in the adjacent cartilage [61]. Increased expression of proinflammatory cytokines in cartilage, synovial membrane and subchondral bone are believed to be linked to the development and progression of structural changes in the OA joint [62]. Inflammatory signals activate inflammasome-dependent responses and caspases, predominantly caspase-1, which cleave the inactive

Pharmacological targets of autophagy

Augmentation of autophagy via inhibition of the TOR signaling pathway by genetic or pharmacological intervention extends lifespan, indicating that the further development of interventions targeting mTOR represents a strategy for the treatment and prevention of age-related diseases [68]. Moreover, since autophagy is a critical protective mechanism against mitochondrial dysfunction, pharmacologic interventions that enhance autophagy may have chondroprotective activity in cartilage degenerative

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No.81272034, 81402224 and 81501923), the Provincial Science Foundation of Hunan (No.2015JJ3139), the Scientific Research Project of Science and Technology Bureau of Hunan Province (2012FJ6001), the Scientific Research Project of Science and Technology Office of Changsha City (K1203040-31), the Scientific Research Project of Health and Family Planning Commission of Hunan Province (B2014-12), the Hunan Provincial

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ReviewAutophagy in osteoarthritis

Abstract

Introduction

Section snippets

Definition of autophagy

The basic process of autophagy

Regulatory factors

Expression of autophagy in OA

Hypoxia, mechanical injury and autophagy

Inflammation and autophagy

Pharmacological targets of autophagy

Disclosure of interest

Acknowledgments

Osteoarthritis Cartilage

Cell

Febs Lett

Cell

J Biol Chem

Mol Aspects Med

Dev Cell

Biochim Biophys Acta

Curr Biol

Biochimie

Febs Lett

Curr Opin Cell Biol

J Biol Chem

J Biol Chem.

Cell

Curr Opin Cell Biol

Int J Biochem Cell Biol

J Biol Chem

Maturitas

J Biol Chem

Cell

Joint Bone Spine

Osteoarthritis Cartilage

J Biol Chem

Osteoarthritis Cartilage.

Osteoarthritis Cartilage

Biomaterials

Osteoarthritis

BMJ

Why is osteoarthritis an age-related disease?

Best Pract Res Clin Rheumatol

Physiological functions of autophagy

Curr Top Microbiol Immunol

Autophagy fights disease through cellular self-digestion

Nature

Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes

Autophagy

The molecular machinery of autophagy: unanswered questions

J Cell Sci

The regulation of autophagy – unanswered questions

J Cell Sci.

TOR signaling in mammals

J Cell Sci

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

Nat Cell Biol

Review
Autophagy in osteoarthritis