Osteoporosis is a disease that causes bones to become less dense and more porous and brittle. This significantly increases the risk of fracture. As people age, their risk of developing osteoporosis increases. This is because the balance between bone generation and bone resorption shifts with age. By the time most people reach their 30s, their bone density has peaked. After that, bone density declines as the balance gradually favors resorption over generation. According to the International Osteoporosis Foundation (IOF), 1 in 3 women and 1 in 5 men over the age of 50 will experience a bone fracture due to osteoporosis. The IOF also estimate that around 75 million people in the United States, Europe and Japan have osteoporosis and that leads to more than 8.9 million bone fractures per year worldwide. Recent research has uncovered a cell mechanism that could help explain why smoking, alcohol, and other modifiable factors could raise the risk of developing the bone disease osteoporosis.
Scientists find a cell mechanism that could explain why certain lifestyle factors, such as smoking, increase the risk of osteoporosis.The mechanism spurs a cell type in the immune system to turn into osteoclasts, which are a type of cell that resorbs, or dissolves, bone. It appears that mitochondria, the cellular powerhouses, send out a signal that triggers this process when under stress. When this happens in the mitochondria of macrophages, the cells turn into osteoclasts. Macrophages are prolific immune cells that remove cell waste and foreign objects by swallowing and digesting them. The researchers behind the discovery hail from the University of Pennsylvania and the Icahn School of Medicine at Mount Sinai in the city of New York.
Senior study author Narayan Avadhani, a professor of Biochemistry at Penn’s School of Veterinary Medicine, explained: “Some of the environmental factors, such as smoking, drinking alcohol, and certain medications, that can impair the function of mitochondria, also appear to raise the risk of osteoporosis. We have found either in cell cultures and mice with dysfunctional mitochondria, that when mitochondrial function is affected, it not only affects energy production but also triggers a type of stress signaling that induces the overproduction of osteoclasts”.
In their study paper, the authors write that the mitochondria-to-nucleus retrograde signaling (MtRS) pathway helps cells to adapt to stress. An earlier investigation had already led them to discover that a way of triggering this pathway can induce macrophages to differentiate into osteoclasts that resorb bone. To explore how mitochondrial damage might be involved, they ran some experiments on laboratory-cultured mouse macrophages. They induced damage in the macrophages by disrupting an enzyme called cytochrome oxidase C, which helps to regulate mitochondrial energy production. As a results, oxidative stress is enhanced and a gene expression response is mediated by transcription factors like NF-kB and NF-AT2. This caused the macrophages to release various inflammatory cytokines that not only triggered inflammation but also appeared to prompt the cells to differentiate into osteoclasts.
This step is promoted by another cytokine called RANK-L. Bone generation releases RANK-L, which triggers bone resorption and keep the balance. However, when the damaged mitochondria sent out signals, macrophages continued to differentiate into osteoclasts, promoting bone resorption even when there wasn’t much RANK-L around. The process was blocked by a molecule called LMT-28, interfering with the activity of the inflammatory cytokine IL-6. The team published their research in a paper on the FASEB Journal; they are now considering doing further studies to find out if preserving mitochondrial function could reduce the risk of osteoporosis.
- Edited by Dr. GIanfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Angireddy R et al., Avadhani NG. FASEB J. 2019 May 7.
Wang WD et al. Eur Rev Med Pharmacol Sci. 2018; 22(23).
Jackson M et al. PLoS One. 2018 Dec; 13(12):e0209489.
Guha M et al. BBA Mol Basis Dis. 2018; 1864(4 Pt A):1060.