Bone is constantly remodeled throughout life through the actions of osteoblasts, cells that build bone, and osteoclasts, cells that break down bone. The proximate cause of osteoporosis, the age-related loss of bone mass and strength, is a growing imbalance between these cell types that favors osteoclasts. Why does this happen? Chronic inflammation generated by the presence of senescent cells appears to be one cause, as cells react to inflammation in ways that favor osteoclast ativity over osteoblast activity. Researchers here provide evidence for the age-related decline in mitochondrial function to be important as well, another mechanism that ensures more osteoclasts than osteoblasts are introduced into bone tissue.
Some risk factors for osteoporosis such as being older and female or having a family history of the condition cannot be avoided. But others can, like smoking cigarettes, consuming alcohol, taking certain medications, or being exposed to environmental pollutants. But until now researchers haven't gained a firm picture of how these exposures link up with bone loss. A new study reveals a mechanism by which these factors and osteoporosis may be linked. Damage to mitochondria - key cellular organelles and energy generators - leads to a surge in the creation of cells called osteoclasts, which are responsible for breaking down bone.
The scientists took a close look at how problems with mitochondria affected a type of immune cell known as macrophages. Macrophages are a front line for the immune system, engulfing and digesting foreign invaders to the body. But macrophages can also diversify, transforming into osteoclasts when the circumstances are right. To understand how mitochondrial damage could be linked to osteoporosis through the work of macrophages, the researchers induced damage to a key enzyme responsible for energy production in mitochondria, cytochrome oxidase C, in lab-grown mouse macrophages. Doing so led the macrophages to release a variety of signaling molecules associated with an inflammatory reaction and also seemed to encourage them to go down the path toward becoming osteoclasts.
Looking closely at what was going on, they observed an anomaly with a key molecule, RANK-L, that helps regulate the bone-rebuilding process and is released by bone-building cells as a means of inducing bone break-down. When mitochondria were damaged, they underwent stress signaling and transformed into osteoclasts at a much faster rate, even when RANK-L levels were low. These osteoclasts led to greater rates of bone resorption, or break down. The researchers confirmed their findings in a mouse model, showing that animals with a mutation that leads to dysfunctional mitochondria had increased production of osteoclasts. Because some of the same environmental risk factors that seem to promote osteoporosis, like smoking and some pharmaceuticals, can also impact mitochondrial function, the team posits that this stress signaling might be the pathway by which they are acting to affect bone health.