Posted 22 July 2024 - 04:43 PM
In iScience, researchers have explained how physical mechanics can alter mitochondrial function in a way that leads to osteoarthritis.
When simple physics affects biology
Previous work has pinpointed abnormal mechanical loading, which occurs when joints are placed under excessive stresses in ways that they were not meant to handle, as a key driver of osteoarthritis [1]. This phenomenon can lead to the death or senescence of chondrocytes, the cells responsible for creating cartilage [2].
The microenvironment of the extracellular matrix (ECM) plays a strong role in the metabolism of chondrocytes [3]. This microenvironment can cause these cells’ mitochondria to uptake calcium [4], and in osteoarthritis, mineral particles begin to form on the joints, after which fibers and packed material are gradually pushed into the joints [5].
Mitochondrial dysfunction brought on by mechanical stresses has been found to be a core component of osteoarthritis [6], and these researchers have noted a downstream pathway: the stressed mitochondria communicate with the nucleus in a way that leads to the demethylation of H3K27me3, a key component of epigenetics [7].
The problems with stiffness
For their first experiment, the researchers used a gel substrate at three different stiffnesses and then grew an established line of chondrocytes in it. The stiffer the gel was, the more calcium was taken up by the chondrocytes. Genes related to stress in protein processing machinery (the endoplasmic reticulum) were upregulated as well.
The cells grown in stiffer conditions also had a decrease in Col2a1, a gene related to the formation of more complex molecules (anabolism), while Mmp13, a gene related to the breaking down of those molecules (catabolism), was increased. This implies that the same thing may be happening in vivo: that increased stress encourages chondrocytes to break down, rather than form, cartilage. Chondrocytes under stiffer conditions are also more prone to death by apoptosis.
The researchers also observed how mitochondria fail with increasing stiffness. At the lightest stiffness, mitochondria formed a normal network, doubling that stiffness broke up that network, and tripling it caused mitochondrial fragments and rings instead of a network of any kind. Mitochondrial division-related proteins increased, and fusion-related proteins decreased, with stiffness; additionally, the mitochondria were less efficient at producing energy.
Intracellular calcium was found to be key to this process. When intracellular calcium was removed, mitochondria under high-stiffness conditions functioned very closely to those under low-stiffness conditions, and they regained some of their energy production capacity.
Pinpointing the dysfunction
The increase in calcium released from the mitochondria increased their membranes’ permeability, which led to an increase in the expression of Phf8. This, the researchers found, was directly related to the demethylation of H3K27me3. Silencing Phf8 prevented this increase in demethylation brought on by stiffness.
These findings were confirmed in mice. An RNA silence of Phf8.was injected into the joints.of mouse model of osteoarthritis. The injected mice had more stable cartilage, more normal mitochondrial fusion and fission, and less demethylation of H3K27me3.
While there was no human testing of Phf8 involved, the researchers did confirm, through cartilage samples taken from human volunteers, that stiffness of the ECM was directly related to the progression of osteoarthritis.
This is an exploratory study, and there was no drug discovery involved; it may prove impractical to use Phf8 as a clinical target, and there may be side effects to this approach. However, in addition to approaches that focus on ECM stiffness itself, such as the well-known problem of cross-linked collagen, targeting how chondrocytes respond to this stiffness may be valuable in treating this crippling ailment.
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Literature
[1] Katz, J. N., Arant, K. R., & Loeser, R. F. (2021). Diagnosis and treatment of hip and knee osteoarthritis: a review. Jama, 325(6), 568-578.
[2] Chang, S. H., Mori, D., Kobayashi, H., Mori, Y., Nakamoto, H., Okada, K., … & Saito, T. (2019). Excessive mechanical loading promotes osteoarthritis through the gremlin-1–NF-κB pathway. Nature communications, 10(1), 1442.
[3] Peng, Z., Sun, H., Bunpetch, V., Koh, Y., Wen, Y., Wu, D., & Ouyang, H. (2021). The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration. Biomaterials, 268, 120555.
[4] Li, X., Kordsmeier, J., Nookaew, I., Kim, H. N., & Xiong, J. (2022). Piezo1 stimulates mitochondrial function via cAMP signaling. FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 36(10), e22519.
[5] Jiang, W., Liu, H., Wan, R., Wu, Y., Shi, Z., & Huang, W. (2021). Mechanisms linking mitochondrial mechanotransduction and chondrocyte biology in the pathogenesis of osteoarthritis. Ageing research reviews, 67, 101315.
[6] Blanco, F. J., Rego, I., & Ruiz-Romero, C. (2011). The role of mitochondria in osteoarthritis. Nature Reviews Rheumatology, 7(3), 161-169.
[7] Peña-Oyarzun, D., Rodriguez-Peña, M., Burgos-Bravo, F., Vergara, A., Kretschmar, C., Sotomayor-Flores, C., … & Criollo, A. (2021). PKD2/polycystin-2 induces autophagy by forming a complex with BECN1. Autophagy, 17(7), 1714-1728.
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