BONE’S BEST-KEPT SECRET: UNDERSTANDING OF BONE HEALTH AND IMMUNE FUNCTION

 Bone is far more than a static structure; it is a living tissue, constantly undergoing remodeling to maintain its strength, respond to injury, and support various biological processes. This delicate balance between bone resorption (breakdown) and bone formation is governed by a finely-tuned system involving multiple cells and signaling molecules. One of the most intriguing players in this system is soluble receptor activator of nuclear factor-κB ligand (sRANKL), which plays a key role in both bone and immune health.

RANKL exists in two forms: membrane-bound (mRANKL) and soluble (sRANKL). Both bind to a receptor known as RANK on the surface of osteoclast precursors (cells responsible for breaking down bone), but their modes of action differ. While mRANKL works through direct cell-to-cell contact, sRANKL diffuses in the extracellular environment, impacting various processes related to both bone resorption and the immune system. Membrane-bound RANKL (mRANKL) is highly effective in promoting osteoclastogenesis—the formation of osteoclasts that demineralize bone. However, sRANKL, though less potent in this process, is far from irrelevant. Its role in conditions like osteoporosis, periodontitis, and inflammatory diseases highlights its importance in maintaining bone health and immune balance.

Recent research from Ikeda et al. identified three isoforms of RANKL (RANKL1, RANKL2, and RANKL3), which further complicates the story. While RANKL1 and RANKL2 are membrane-bound and play a more direct role in bone resorption, RANKL3 is thought to act as the soluble form. Understanding these isoforms has opened new avenues for investigating how bone cells, immune cells, and even certain cancers interact.

Though mRANKL is more effective at forming osteoclasts, sRANKL’s ability to travel through the extracellular space allows it to play a crucial role in maintaining bone integrity. Studies have shown that a deficiency in sRANKL leads to increased bone mass and reduced osteoclast numbers, emphasizing its role in balancing bone resorption. Even though it is less effective at triggering osteoclastogenesis compared to mRANKL, sRANKL contributes to bone health in ways that are still being unraveled.

In particular, TRAF (tumor necrosis factor receptor-associated factor) signaling—mediated through TRAF6—activates pathways like JNK, MAPKs, and NF-κB, which are critical in turning immature osteoclasts into bone-resorbing powerhouses. The intricate dance between mRANKL and sRANKL ensures that osteoclasts are made where they’re needed, without tipping the balance too far into either excessive bone loss or formation.

But bone remodeling isn’t just about resorption; it’s also about building new bone, a process primarily carried out by osteoblasts. Emerging research suggests that sRANKL might also play a role in promoting bone formation. When sRANKL interacts with secreted frizzled-related protein-1 (sFRP-1)—an inhibitor of the bone-forming Wnt pathway—it removes this inhibition, thereby allowing bone formation to proceed. Interestingly, sRANKL also seems to activate “reverse signaling” in osteoblasts, which engages the mTORC1 pathway, promoting the activity of the transcription factor RUNX2, a master regulator of osteoblast differentiation. This interplay between bone resorption and formation showcases how finely balanced bone homeostasis truly is.

Bone and immune health are deeply interconnected, a field known as osteoimmunology. sRANKL, along with its membrane-bound cousin, plays a critical role here. T cells, key players in the immune response, secrete RANKL in response to inflammation. This not only influences osteoclast formation but also impacts immune responses by regulating molecules like CD40 and enhancing dendritic cell survival. T cells produce sRANKL, which can both promote and inhibit osteoblast activity by engaging in forward and reverse signaling mechanisms. At the same time, osteoprotegerin (OPG)—a decoy receptor secreted by cells like T cells—acts to inhibit RANKL's activity, adding another layer of regulation.

The dual role of sRANKL in both bone formation and resorption means that its dysregulation can contribute to various diseases. High sRANKL levels are seen in conditions like osteoporosis, arthritis, and even certain cancers. On the flip side, osteopetrosis, a condition marked by overly dense bones, has been linked to reduced sRANKL activity. Researchers are actively investigating therapies that can modulate sRANKL activity. For instance, using osteoprotegerin (OPG) or other inhibitors to reduce bone resorption in conditions like osteoporosis may offer a way to preserve bone health without stifling the body’s ability to remodel bone.

When it comes to fractures, membrane-bound RANKL (mRANKL) is generally seen as the critical player. However, sRANKL may still have a role in fracture healing, especially in certain physiological conditions. Research has shown that serum sRANKL levels may predict fracture risk, but its direct impact on fracture repair remains uncertain. In healthy bones, OPG works to curb excessive bone resorption by sRANKL. However, in cases of osteoporosis, this balance is often disrupted, leading to increased fracture risk. Some studies have even shown that low levels of sRANKL correlate with higher fracture incidence, though more research is needed to fully clarify this relationship.

As we continue to uncover the multiple roles sRANKL plays in bone and immune health, the potential for targeted therapies grows. Could modulating sRANKL levels become a treatment for bone diseases? Therapies that silence sRANKL signaling, or alternatively, enhance it in cases like osteopetrosis, may open new doors for bone health management. sRANKL is far more than just a promoter of bone breakdown—it’s a key player in maintaining bone health, supporting immune function, and responding to inflammation. As research continues, we’re likely to see new therapeutic strategies emerge that can fine-tune sRANKL’s activity, offering hope for people with conditions like osteoporosis, arthritis, and beyond. 

REFERENCE:

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https://doi.org/10.1016/j.cyto.2021.155559

IMAGE CREDITS:

https://en.wikipedia.org/wiki/Bone

https://www.sciencedirect.com/science/article/abs/pii/S1043466621001393