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Study Sheds Light on How Cigarette Smoke, Pollutants Can Cause Osteoporosis

Jaime Rosenberg
Damage to mitochondria, which can occur from exposure to cigarette smoke and environmental pollutants, leads to a surge in the creation of osteoclasts that break down bone.
Characteristics like older age and being female are linked to an increased risk of osteoporosis, but the condition is also associated with modifiable risk factors, such as smoking cigarettes and being exposed to environmental pollutants. However, researchers have historically been unable to identify the link between these factors and osteoporosis.

Now, a new study is offering a possible explanation, finding that damage to mitochondria, which occurs as a result of these modifiable risk factors, leads to a surge in the creation of osteoclasts that break down bone.

The study researchers induced damage to cytochrome oxidase C—a key enzyme responsible for energy production in mitochondria—in lab-grown mouse microphages in order to understand how microphages could provide the missing link between mitochondrial damage and osteoporosis.

Macrophages represent the first line of defense for the immune system, locating and digesting foreign invaders to the body, such as bacteria. These cells can also transform into osteoclasts under certain circumstances.

“In a normal individual, the process of bone degradation and rebuilding proceeds in a very balanced way, but in some people they somehow produce a lot more osteoclasts, and this leads to bone loss and osteoporosis,” said Narayan Avadhani, BSc, PhD, Harriot Ellison Woodward Professor of Biochemistry, Department of Biomedical Sciences, University of Pennsylvania, and senior author of the study, in a statement.

By inducing damage to cytochrome oxidase C, the researchers found that the macrophages released a variety of signaling molecules associated with an inflammatory reaction. The intervention also seemed to encourage the cells to become osteoclasts. The researchers observed that these responses occurred even with low levels of RANK-L, a key molecule that helps regulate the bone-rebuilding process and is released by bone-building cells as a means of encouraging bone breakdown.

“In some respects, mitochondrial stress signaling may even be replacing RANK-L,” said Avadhani. “That we don’t know now, but we plan to look into that further.”

These findings were confirmed in a mouse model, which demonstrated that animals with a mutation that leads to mitochondrial dysfunction had increased production of osteoclasts. The mouse model also revealed that their microphages had higher levels of phagocytosis, in which the cells engulf and digest invaders. According to the researchers, this enhanced physiological ability could be responsible for some of the other physiological problems that can occur in people with mitochondrial damage.

As some environmental risk factors that seem to increase the risk of osteoporosis, such as smoking, can also impact mitochondrial function, the researchers suggested that this stress signaling might be a pathway by which they are affecting bone health.


Angireddy R, Kazmi H, Srinivasan S, et al. Cytochrome c oxidase dysfunction enhances phagocytic function and osteoclast formation in macrophages [published online May 7, 2019]. FASEB J. doi: 10.1096/fj.201900010RR. 

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