Bones may seem solid, but their insides are filled with honeycomb-like spaces. Bone tissue is continuously being broken down and rebuilt. Some cells are responsible for forming new bone tissue while others break down existing bone and release its minerals.
As we age, the rate at which we lose bone tissue exceeds the rate at which we produce it. This results in the tiny holes within bones enlarging and the dense outer layer becoming thinner leading to reduced bone density. Therefore, dense bones become more thin and already flexible bones become even more so. When bone density decreases significantly, this condition is known as osteoporosis. It is estimated that over 10 million people nationwide suffer from osteoporosis.
While it is normal for bones to break in severe accidents, adequately dense bones can usually withstand most falls. However, bones weakened by osteoporosis are more prone to fractures. The hormone estrogen plays a crucial role in bone formation and regeneration. After menopause, a woman's estrogen levels decrease leading to fast bone loss which is why osteoporosis is most prevalent among older women. However, men are also affected by osteoporosis.
Dr. Eric Orwoll, a physician-researcher at Oregon Health and Science University who specializes in osteoporosis notes that almost one-third of all hip fractures occur in men, but osteoporosis in men is often overlooked or minimized. According to Orwoll, men tend to have worse outcomes than women following a hip fracture.
Osteoporosis: A Growing Threat to Skeletal Health
- Understanding the Condition: Osteoporosis is a condition marked by the development of delicate and easily breakable bones by pose a significant threat to skeletal health. Bones, being the primary structural support of the human body are crucial for maintaining overall function and flexibility. When bone mass diminishes, this support weakens leading to reduced functionality and a decrease in the quality of life.
- Healthcare Implications: As the global population ages, the incidence of osteoporosis is rising, placing a substantial burden on healthcare systems, particularly in terms of long-term care. This situation highlights the urgency to understand the underlying mechanisms of osteoporosis and to develop effective treatments that can address its long-term effects.
The Role of Bone Cells
Two types of cells, osteoblasts and osteoclasts are essential for the maintenance and remodelling of bone tissue. Osteoblasts are responsible for forming new bone, while osteoclasts break down old or damaged bone. An imbalance, particularly an increase in osteoclast activity leads to bone mass loss, as seen in conditions like osteoporosis, rheumatoid arthritis, and bone metastases. Osteoclasts originate from macrophages or monocytes, types of immune cells suggesting that targeting their differentiation could be a therapeutic strategy to prevent bone loss.
Molecular Pathways and Bone Re-modelling
Despite knowing the roles of osteoblasts and osteoclasts, the exact molecular pathways that govern bone remodelling remain unclear. Recent research by Professor Tadayoshi Hayata and his team from Tokyo University of Science has provided new insights into this complex process. They focused on the differentiation of macrophages into osteoclasts, stimulated by the receptor activator of nuclear factor kappa B ligand (RANKL). Additionally, they explored how bone morphogenetic protein (BMP) and transforming growth factor (TGF)-β signalling pathways influence this differentiation process.
Groundbreaking Research on Osteoclast Differentiation
In their upcoming study, set to be published on July 30, 2024, in Biochemical and Biophysical Research Communications, the researchers investigated the role of Ctdnep1 which is an enzyme known to suppress BMP and TGF-β signalling. Their findings revealed that RANKL acts as an "accelerator" for osteoclast differentiation. Professor Hayata explains, "Driving a car requires not only the accelerator but also the brakes. Here, we find that Ctdnep1 functions as a 'brake' on osteoclast cell differentiation." This discovery highlights the potential of Ctdnep1 as a therapeutic target to control bone loss in osteoporosis.
The study by Professor Hayata and his team provides a deeper understanding of the molecular regulation of bone remodelling by offering hope for new therapeutic approaches to treat osteoporosis. By targeting the differentiation of osteoclasts, it may be possible to develop treatments that effectively mitigate bone loss thereby improving the quality of life for individuals affected by this draining condition.
Examination of Ctdnep1 Expression
Researchers investigated the expression of the Ctdnep1 gene in mouse-derived macrophages by comparing those treated with RANKL to untreated control cells. They observed that Ctdnep1 expression did not change upon RANKL stimulation. However, in macrophages and osteoclasts, Ctdnep1 was found in the cytoplasm in granular form rather than its usual peri-nuclear location in other cell types. This suggests a specific cytoplasmic role for Ctdnep1 in the differentiation of osteoclasts.
Effects of Ctdnep1 reduction
When the expression of Ctdnep1 was reduced, there was an increase in tartrate-resistant acid phosphatase-positive (TRAP) osteoclasts with TRAP being a marker for differentiated osteoclasts. This reduction also led to higher expression of key differentiation markers such as 'Nfatc1', which is a crucial transcription factor for osteoclast differentiation induced by RANKL. These results indicate that Ctdnep1 functions as a negative regulator of osteoclast differentiation by effectively acting to stop the excessive release of any acids in our body.
Impact on Bone Reabsorption
Additionally, Ctdnep1 reduction resulted in greater absorption of calcium phosphate by indicating that Ctdnep1 suppresses bone reabsorption. This suggests that reducing Ctdnep1 expression enhances the activity of osteoclasts in breaking down bone material.
Signalling Pathways
Interestingly, reducing down Ctdnep1 did not affect BMP and TGF-b signalling pathways. However, cells deficient in Ctdnep1 showed higher levels of phosphorylated proteins which are activated components of the RANKL signalling pathway. This implies that Ctdnep1’s suppressive effect on osteoclast differentiation is likely through the negative regulation of the RANKL signalling pathway and Nfatc1 protein levels, rather than through BMP and TGF-b signalling.
Broader Implications
These findings offer new insights into osteoclast differentiation and highlight potential therapeutic targets for treating conditions involving bone loss due to excessive osteoclast activity. Beyond bone metabolism, Ctdnep1 is also implicated in medulloblastoma, a type of childhood brain tumour. Therefore, the researchers are hopeful that their study could extend to other human diseases beyond those affecting bone health.
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