In iScience, researchers have defined how physical mechanics can alter mitochondrial function in a way that leads to osteoarthritis.
When easy physics impacts biology
Earlier work has pinpointed irregular mechanical loading, which happens when joints are positioned underneath extreme stresses in ways in which they weren’t meant to deal with, as a key driver of osteoarthritis [1]. This phenomenon can result in the loss of life or senescence of chondrocytes, the cells accountable for creating cartilage [2].
The microenvironment of the extracellular matrix (ECM) performs a robust position within the metabolism of chondrocytes [3]. This microenvironment may cause these cells’ mitochondria to uptake calcium [4], and in osteoarthritis, mineral particles start to kind on the joints, after which fibers and packed materials are steadily pushed into the joints [5].
Mitochondrial dysfunction introduced on by mechanical stresses has been discovered to be a core part of osteoarthritis [6], and these researchers have famous a downstream pathway: the confused mitochondria talk with the nucleus in a manner that results in the demethylation of H3K27me3, a key part of epigenetics [7].
The issues with stiffness
For his or her first experiment, the researchers used a gel substrate at three completely different stiffnesses after which grew a longtime line of chondrocytes in it. The stiffer the gel was, the extra calcium was taken up by the chondrocytes. Genes associated to emphasize in protein processing equipment (the endoplasmic reticulum) had been upregulated as effectively.
The cells grown in stiffer circumstances additionally had a lower in Col2a1, a gene associated to the formation of extra complicated molecules (anabolism), whereas Mmp13, a gene associated to the breaking down of these molecules (catabolism), was elevated. This means that the identical factor could also be taking place in vivo: that elevated stress encourages chondrocytes to interrupt down, reasonably than kind, cartilage. Chondrocytes underneath stiffer circumstances are additionally extra susceptible to loss of life by apoptosis.
The researchers additionally noticed how mitochondria fail with rising stiffness. On the lightest stiffness, mitochondria shaped a standard community, doubling that stiffness broke up that community, and tripling it brought on mitochondrial fragments and rings as an alternative of a community of any sort. Mitochondrial division-related proteins elevated, and fusion-related proteins decreased, with stiffness; moreover, the mitochondria had been much less environment friendly at producing power.
Intracellular calcium was discovered to be key to this course of. When intracellular calcium was eliminated, mitochondria underneath high-stiffness circumstances functioned very carefully to these underneath low-stiffness circumstances, and so they regained a few of their power manufacturing capability.
Pinpointing the dysfunction
The rise in calcium launched from the mitochondria elevated their membranes’ permeability, which led to a rise within the expression of Phf8. This, the researchers discovered, was immediately associated to the demethylation of H3K27me3. Silencing Phf8 prevented this enhance in demethylation introduced on by stiffness.
These findings had been confirmed in mice. An RNA silence of Phf8.was injected into the joints.of mouse mannequin of osteoarthritis. The injected mice had extra secure cartilage, extra regular mitochondrial fusion and fission, and fewer demethylation of H3K27me3.
Whereas there was no human testing of Phf8 concerned, the researchers did verify, by way of cartilage samples taken from human volunteers, that stiffness of the ECM was immediately associated to the development of osteoarthritis.
That is an exploratory research, and there was no drug discovery concerned; it might show impractical to make use of Phf8 as a medical goal, and there could also be unwanted side effects to this method. Nonetheless, along with approaches that concentrate on ECM stiffness itself, such because the well-known drawback of cross-linked collagen, concentrating on how chondrocytes reply to this stiffness could also be worthwhile in treating this crippling ailment.
Literature
[1] Katz, J. N., Arant, Okay. R., & Loeser, R. F. (2021). Prognosis and therapy of hip and knee osteoarthritis: a overview. Jama, 325(6), 568-578.
[2] Chang, S. H., Mori, D., Kobayashi, H., Mori, Y., Nakamoto, H., Okada, Okay., … & Saito, T. (2019). Extreme mechanical loading promotes osteoarthritis by way of the gremlin-1–NF-κB pathway. Nature communications, 10(1), 1442.
[3] Peng, Z., Solar, 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 operate by way of 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 within the pathogenesis of osteoarthritis. Ageing analysis opinions, 67, 101315.
[6] Blanco, F. J., Rego, I., & Ruiz-Romero, C. (2011). The position of mitochondria in osteoarthritis. Nature Opinions 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 posh with BECN1. Autophagy, 17(7), 1714-1728.
