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Review
. 2023 Apr 22;13(5):721.
doi: 10.3390/biom13050721.

An Integrated View of Stressors as Causative Agents in OA Pathogenesis

Joseph S Floramo  1 , Vladimir Molchanov  1 , Huadie Liu  1 , Ye Liu  1 , Sonya E L Craig  1 , Tao Yang  1
Affiliations
Review

An Integrated View of Stressors as Causative Agents in OA Pathogenesis

Joseph S Floramo et al. Biomolecules. .

Abstract

Cells in the body are exposed to dynamic external and internal environments, many of which cause cell damage. The cell's response to this damage, broadly called the stress response, is meant to promote survival and repair or remove damage. However, not all damage can be repaired, and sometimes, even worse, the stress response can overtax the system itself, further aggravating homeostasis and leading to its loss. Aging phenotypes are considered a manifestation of accumulated cellular damage and defective repair. This is particularly apparent in the primary cell type of the articular joint, the articular chondrocytes. Articular chondrocytes are constantly facing the challenge of stressors, including mechanical overloading, oxidation, DNA damage, proteostatic stress, and metabolic imbalance. The consequence of the accumulation of stress on articular chondrocytes is aberrant mitogenesis and differentiation, defective extracellular matrix production and turnover, cellular senescence, and cell death. The most severe form of stress-induced chondrocyte dysfunction in the joints is osteoarthritis (OA). Here, we summarize studies on the cellular effects of stressors on articular chondrocytes and demonstrate that the molecular effectors of the stress pathways connect to amplify articular joint dysfunction and OA development.

Keywords: DNA damage; chondrocyte; inflammation; mechanical overloading; metabolic stress; oxidative stress; proteostatic stress; signaling pathway.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Stress is a major mediator between associated OA risk factors and pathogenesis. The OA-associated risk factors can serve as the initiator of stress or can promote the accumulation of stress-induced cellular damage or aggravate the vulnerability of joint tissues to these damages.
Figure 2
Figure 2
An integrated view of the molecular synergy among stressors that leads to articular chondrocyte dysfunction and OA pathogenesis. The inner circle represents the hallmarks of OA, including chondrocyte apoptosis, senescence, decline in ECM production, increase in ECM degradation, abnormal chondrocyte differentiation, and inflammation. These OA hallmarks are the consequences of the five major stressors placed in the outer circle. The arrows indicate the interplay of these stressors and their downstream effectors. Note that the oxidative and proinflammatory factors form a central hub (in red) integrating the output of all stressors and aggravating the stress-induced damage with multiple vicious feed-forward loops.
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