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The exact pathophysiology of OA is unknown, but available studies suggest that OA is multifactorial in nature as a result of the interaction of biomechanical, molecular and genetic factors[1]. Inflammation is associated with OA, and inflammation shifts the metabolism of the extracellular matrix (ECM) from a matrix-producing state to a matrix-degrading state, characterized by the production of matrix metalloproteinases (MMP), disintegrases and metalloproteinases, which break down articular cartilage. Degradation of articular cartilage results in the loss of its protective biomechanical characteristics, leading to joint destruction, further inflammation, and progression of OA [2].

The function of mitochondria in chondrocytes and their key role in the pathophysiology of OA have also been intensively studied. Mitochondria perform complex functions within the cell, not only as a source of energy but also as regulators of cell survival and oxidative stress. Mechanisms required for TCA cycling (an efficient system for the generation of high-energy electron carriers) and ETC (site of oxidative phosphorylation) are present in mitochondria. It is well known that OA chondrocytes contain dysfunctional mitochondria, which are characterized by loss of membrane potential, decreased biogenesis, decreased ATP production, decreased membrane potential, and increased production of destructive ROS[3]. OA chondrocytes also have decreased mitochondrial biogenesis, which correlates with an increased activity of cartilage degradation. Mechanical overloading of the joints also leads to overproduction of mitochondrial superoxide in cartilage, similar to the effects of inflammatory stimuli. It is suspected that mitochondrial changes are related to inflammatory signaling in chondrocytes[4].

Stimulation of inflammatory cytokines and subsequent NF-kB activation leads to a dramatic decrease in oxidative phosphorylation in human and mouse chondrocytes, which is consistent with the previously noted increase in glycolytic activity. In addition, stimulation of IL-1b or TNF-a inhibits the activity of complex 1 in the ETC. These factors also markedly increase superoxide production by chondrocyte mitochondria in vitro. Elevated mitochondrial production of ROS leads to a potentially destructive state of the cell, overwhelming antioxidant systems such as superoxide dismutase (SOD)[5].

Given that dysfunctional mitochondria promote pathological processes such as ROS production, inhibition of these systems should prevent degenerative changes. Inhibition of ETC activity in the presence of inflammatory stimuli with antimycin A or rotenone reduces inflammatory gene expression by lowering IkB-z protein levels. Similarly, the ETC inhibitor isopentobarbital or the antioxidant N-acetylcysteine prevents OA in a large animal model of intra-articular fracture by decreasing pathologic ROS.[6] Other studies have demonstrated that mitochondrial mitochondrial function can be reduced by the addition of galactose to salvage mitochondrial function reduces the inflammatory response in chondrocytes, suggesting that mitochondrial dysfunction may be induced by reducing oxidative stress. Other mitochondrionally active target molecules have also been used as possible therapies in preclinical models of OA. For example, 4-MU was able to improve the mitochondrial function of chondrocytes and thereby reduce cartilage degradation[7]. These studies have demonstrated that in the inflammatory conditions, both ETC activity and mitochondrial dysfunction in general may be pathologic, and restoration of mitochondrial physiological activity may be beneficial.

Treatments can also reprogram mitochondria to improve their function, thereby reducing cartilage degradation. For example, bone morphogenetic protein (BMP)2 signaling has been shown to promote mitochondrial metabolism and oxidative phosphorylation, and replacing glucose in the culture medium with galactose promotes mitochondrial respiratory activity in chondrocytes. Similarly, compounds such as dichloroacetic acid (DCA) and 4-MU that inhibit glycolysis and promote mitochondrial respiration lead to reduced expression of inflammatory genes. In addition, mitochondrial biogenesis is also important for chondrocyte health. For example, activation of the AMPK-Sirt1 axis may also be protective against OA[9].

Reference

1. Cui, A., Li, H., Wang, D., Zhong, J., Chen, Y., & Lu, H. (2020). Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies. EClinicalMedicine, 29-30, 100587.

2. Arra, M., Swarnkar, G., Alippe, Y., Mbalaviele, G., & Abu-Amer, Y. (2022). IκB-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology. Bone research, 10(1), 12.

3. Ansari, M. Y., Ahmad, N., Voleti, S., Wase, S. J., Novak, K., & Haqqi, T. M. (2020). Mitochondrial dysfunction triggers a catabolic response in chondrocytes via ROS-mediated activation of the JNK/AP1 pathway. Journal of cell science, 133(22), jcs247353.

4. Li, K., Ji, X., Seeley, R., Lee, W. C., Shi, Y., Song, F., Liao, X., Song, C., Huang, X., Rux, D., Cao, J., Luo, X., Anderson, S. M., Huang, W., & Long, F. (2022). Impaired glucose metabolism underlies articular cartilage degeneration in osteoarthritis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 36(6), e22377.

5. Bolduc, J. A., Collins, J. A., & Loeser, R. F. (2019). Reactive oxygen species, aging and articular cartilage homeostasis. Free radical biology & medicine, 132, 73–82.

6. Mao, X., Fu, P., Wang, L., & Xiang, C. (2020). Mitochondria: Potential Targets for Osteoarthritis. Frontiers in medicine, 7, 581402.

7. Wang, L., Shan, H., Wang, B., Wang, N., Zhou, Z., Pan, C., & Wang, F. (2018). Puerarin Attenuates Osteoarthritis via Upregulating AMP-Activated Protein Kinase/Proliferator-Activated Receptor-γ Coactivator-1 Signaling Pathway in Osteoarthritis Rats. Pharmacology, 102(3-4), 117–125.

8. Liu, H., Li, Z., Cao, Y., Cui, Y., Yang, X., Meng, Z., & Wang, R. (2019). Effect of chondrocyte mitochondrial dysfunction on cartilage degeneration: A possible pathway for osteoarthritis pathology at the subcellular level. Molecular medicine reports, 20(4), 3308–3316.

9. Wang, D. D., He, C. Y., Wu, Y. J., Xu, L., Shi, C., Olatunji, O. J., Zuo, J., & Ji, C. L. (2022). AMPK/SIRT1 Deficiency Drives Adjuvant-Induced Arthritis in Rats by Promoting Glycolysis-Mediated Monocytes Inflammatory Polarization. Journal of inflammation research, 15, 4663–4675.