As we age, our bones gradually lose density and become more prone to fractures and other injuries. For physicians and scientists, finding effective ways to protect and improve bone health is a major challenge, especially given the growing prevalence of conditions like osteoporosis.
mTOR Driven Bone Loss and Osteoclast Hyperfunction
Osteoclasts are the cells responsible for breaking down bone tissue. In healthy individuals, osteoclasts work alongside other types of bone cells called osteoblasts to maintain a balance between the formation and resorption of bone tissue. However, in individuals with osteoporosis, the activity of osteoclasts is increased relative to that of osteoblasts, leading to a net loss of bone tissue.
The hyperactivity of osteoclasts is a classic example of Mikhail Blagosklonny’s theory of hyperfunctionality and mTOR-driven aging. According to Blagosklonny, cellular dysfunction resulting from the overactivity of mTOR is a defining characteristic of most age-related diseases.
mTOR (mechanistic target of rapamycin) is a protein kinase that plays a crucial role in regulating cell growth, metabolism, and other cellular processes. It is involved in coordinating the response of cells to various stimuli, such as nutrient availability, stress, and growth factors.
You can think of mTOR as the air-traffic controller for cellular growth. When a cell is exposed to growth stimuli or an excess of nutrients, mTOR coordinates cellular protein synthesis and cell growth.
The mTOR pathway is a key signaling pathway that is dysregulated in many age-related diseases, including osteoporosis.
When mTOR is overactive, cell growth becomes excessive, and cell output becomes toxic to the tissue. The defining characteristic of these dysfunctional cells is that they grow excessively large, over-excrete toxic proteins, chemicals, and inflammatory molecules, and cause excessive tissue growth by releasing excessive growth factors and mitogens (molecules that cause cells to replicate).
In the case of osteoporosis, the hyperactivity of osteoclasts is a classic example of this phenomenon. In individuals with osteoporosis, the activity and size of osteoclasts is increased relative to that of osteoblasts, leading to a net loss of bone tissue. The over-activated mTOR pathway drives this hyperactivity or hyperfunctionality of osteoclasts.
Recent research has focused on developing treatments that can help to reduce the hyperactivity of osteoclasts and rebalance the bone remodeling process. One such approach is to target the mTOR pathway using drugs like rapamycin.
Let’s see how rapamycin rebalances activity between osteoclasts, osteoblasts, and osteocytes to promote healthy bone growth.
Bone Growth Mechanisms of Rapamycin
1. Inhibiting Osteoclast Hyperfunction
The overactivation of mTOR in osteoclasts leads to the suppression of cell death (apoptosis) and the promotion of cell growth and survival. This increases bone breakdown in osteoporosis as more osteoclasts survive and remain hyperactive.
Senescent osteoclasts accumulate in bone tissue as we get older. These dysfunctional senescent cells are damaged and no longer functional. Senescent osteoclasts excrete high levels of inflammatory molecules called cytokines.
Some cytokines, such as IL-6 and TNFα, have been found to activate mTOR signaling and amplify the formation and activity of osteoclasts. These elevated inflammatory molecules compound the negative effects of hyperfunctional osteoclasts by excreting more growth factors, which then fuels the growth and creation of more dysfunctional senescent osteoclasts.
To break this cycle, researchers used rapamycin to stop the hyperfunction of osteoclasts and the formation of senescent cells.
Rapamycin is an inhibitor of mTOR signaling, making it a promising tool for treating osteoporosis and periodontal bone loss. By blocking the excessive release of inflammatory molecules like TNFα, which can stimulate osteoclast growth, rapamycin helps to prevent excessive bone resorption and breakdown by osteoclasts.
The researchers found that rapamycin brought the osteoclast activity back to healthy levels, which in turn resulted in increased bone density.
2. Boosting autophagy in osteocytes and osteoblasts leads to healthier bone cells.
Autophagy in Osteoblasts
Rapamycin increases autophagy, the process of cellular ‘self-digestion,’ which removes damaged and dysfunctional molecules and organelles from the cell. Autophagy is a critical lever we have to promote healthy cell function.
The study found that autophagy was a driver in helping to maintain the balance of bone formation and resorption by removing damaged or aged osteoblasts. They found that removing damaged osteoblasts, allows for the creation of new, healthy osteoblasts, ultimately leading to more bone formation.
Autophagy in Osteocytes
The study also found that autophagy also leads to the viability of healthy osteocytes. Osteocytes, which compose 90 to 95% of all bone cells in adults, are the orchestrator of bone remolding by coordinating the functions of osteoblasts and osteoclasts.
As we age, there is a significant decrease in the number of osteocytes, the cells that comprise the majority of bone tissue. This decline is accompanied by an increase in the number of osteocytes undergoing apoptosis, which is a process of programmed cell death of the osteocytes.
Research has shown that the death of osteocytes plays a significant role in age-related bone loss. This is because when osteocytes die, they attract osteoclasts to the site, which then begin to break down and resorb the surrounding bone tissue. This process of resorption leads to a loss of bone density and strength, making the skeleton more fragile and prone to fractures.
Due to their location deep within the bone matrix, osteocytes often live in nutrient-poor and hypoxic (low oxygen) environments. With low nutrients and low oxygen, osteocytes have developed several mechanisms to obtain the nutrients and energy they need to function. One of the most important of these mechanisms is autophagy. Through autophagy, osteocytes digest and recycle some of their own components to generate energy.
When autophagy is blocked, decreased bone mass is seen, increasing the risk of fractures and other bone-related disorders. To understand how autophagy leads to more bone formation, the research team decided to see if they could lower the number of dying osteocytes by inducing autophagy through rapamycin treatment.
The study showed that:
- Rapamycin increased autophagy markers in osteocytes.
- Osteocytes were more viable after rapamycin treatment.
- The rapamycin group had an obvious increase in the mineral absorption rate and a decrease in osteoclasts, the cells that break down bone.
- Levels of osteocalcin, a protein produced by osteoblasts, were higher—indicating more bone formation happening.
- Additionally, the study found that levels of osteocalcin, a protein produced by osteoblasts, were higher, indicating more bone formation, and levels of TRACB, an enzyme produced by osteoclasts, were down, indicating less bone loss.
This suggests that rapamycin-induced mTOR inhibition provides bone growth benefits partially through its promotion of autophagy.
4. Rapamycin-Induced Collagen Production
Collagen is a critical protein for maintaining the structure and integrity of bone tissue. Type I collagen, in particular, is a crucial component of the bone matrix, forming a three-dimensional network of fibers that provides strength and support to the bone.
As we age, the production and quality of collagen in the bone tissue can decline, which can lead to decreased bone density and an increased risk of fractures. In conditions like osteoporosis, this decline in collagen production can be especially pronounced.
One promising approach to treating osteoporosis is to find ways to promote the production of Type I collagen in the bone matrix.
Rapamycin has been found to be effective in increasing the production of Type I collagen, partly by activating the transcription factor Runx2. This protein plays a crucial role in the differentiation of mesenchymal stem cells into osteoblasts, which leads to more bone formation.
Rapamycin may help restore and maintain healthy levels of Type I collagen in the bone by promoting the growth and differentiation of osteoblasts. This may help to slow or even reverse the progression of osteoporosis, reducing the risk of fractures and other related complications.