Bone remodeling process is crucial for balancing metabolic changes between bone formation and bone resorption. Bone remodeling process carried out by two specialized cells such as Osteoblast and Osteoclast. The cell, Osteoblast involved in the bone formation (ossification) and osteoclast production (Osteoclastogenesis), while Osteoclast play a major role in bone resorption (break down). The activities of these both cells secure the skeletal integrity and strength and maintains the blood mineral homeostasis throughout the life; any alterations in bone remodeling process leads to bone disorders.
Some of the main factors involved in the bone remodeling process has been described below.
1. Receptor activator of NFkB ligand (RANKL)
This is a protein ligand molecule (TNF-family cytokine) which express on the membrane of Osteoblast cells. This ligand is essential for osteoclast formation as well as mammary gland and immune cell development. The ligand, RANKL is available in the cell in two forms such as membrane bound or soluble form. Both of these forms deliver a signaling process for formation of osteoclast cells. In the process of Osteoclast formation, RANKL will bind to its receptor RANK (Nuclear factor-kB) and stimulate both proliferation and differentiation of osteoclast progenitor cells.
Research on RANKL
In recent studies (2018) Scientists from University of Arkansas for Medical Sciences, USA, performed experiment on RANKL (either membrane-bound or soluble form), is a important factor in Osteoclast formation. For that, they created the mice, which have sheddase-resistant (the enzyme, protease that show potent RANKL sheddase activity) for RANKL release. Thus, this mouse lack a soluble RANKL in the blood circulation. After their experiment on the mice, they found that deficiency of soluble RANKL did not affect bone structure or mass in developing mice but reduced the osteoclast cell number and increased the cancellous bone mass in adult mice.
However, the bone loss caused by estrogen deficiency is unaffected by the absence of soluble form of RANKL. While, lymphocyte number, lymph node development, and mammary gland development are also unaffected by the lack of soluble RANKL. Finally, they concluded that the membrane-bound form of RANKL is sufficient for most functions of this protein but the soluble form of RANKL is essential for physiological bone remodeling process in adult mice (1).
2. RANK role in bone remodeling process
Receptor activator of NF-κB is a receptor expressed on membrane of osteoclast progenitor cells. When it interacts with RANKL, then that relays the signaling messages to intracellular transcription factors in order to induce the proliferation and differentiation of osteoclasts.
3. Osteoprotegerin for bone remodeling process
Osteoprotegerin (OPG) is a cytokine receptor of the tumor necrosis factor receptor super-family member. OPG is encoded by the gene called TNFRSF11B. OPG receptors protect the bone from excessive breakage (resorption) by inhibiting the process called Osteoclastogenesis. Hence, the OPG also called as Osteoclastogenesis inhibitory factor (OCIF). This inhibition process occurred by binding of OPG to RANKL, the OPG-RANKL complex reduces the available form of RANKL to RANK. Thus, the relative expressions of RANKL and OPG in bones are a major determinants for bone mass and strength maintains. The more concentrations of PGP than RANKL reduces the activity of Osteoclasts thereby reduction of bone remodeling process.
4. Macrophage colony stimulating factor (MCSF) and its function in bone remodeling process
MCSF is one of the essentialia factor involved in bone remodeling process. MCSF is important for proliferation and differentiation of osteoclasts, monocytes, and tissue macrophages. MCSF also play a major role in production and function of lysosomes and formation of ruffled border in Osteoclast cells. Ruffled borders are very important for increasing the surface area of osteoclast cell to facilitate delivery of digestive enzymes and formation of an acidic environment to allow the osteoclast to degrade the bone. Lysosome is very important cellular organelle in osteoclast to digest the engulfed bone fragments. Deficiency of MCSF in the bone tissue result in abnormal bone remodeling.
5. c-Fms (M-CSF receptor) and its function in bone remodeling process
c-Fms is receptor found on the membrane of osteoclast progenitor cells and allows the binding of M-CSF ligand for proliferation of osteoclasts, monocytes, and tissue macrophages.
6. Interleukins and their role in bone remodeling process
Interleukins are cytokines, which are mediators of cellular signaling process. In the case of bone remodeling, interleukins are produced by T-cells to activate the osteoblast cells, which in turn releases the signaling molecule to facilitate the osteoclast proliferation and differentiation (5).
7. Serine-threonine protein kinase Akt role in bone remodeling process
Bone mass and turnover are maintained with equilibrium between bone formation and bone resorption under the control of various external and internal factors. Phosphoinositide-dependent serine-threonine protein kinase Akt is one of the significant factor in the signaling process of potent bone anabolic factors. Low level of Akt expression in osteoblasts and osteoclasts in mice, leads to low-turnover osteopenia due to dysfunctions of both bone cells. Akt was recognized as a crucial modulator for osteoblasts and osteoclasts for promoting their proliferation, differentiation and survival to maintain the bone mass and turnover (bone remodeling process).
- Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss. Nature Communications volume 9, Article number: 2909 (2018).
- Brendan F. Boyce, M.D. and Lianping Xing, M.D., Ph.D. Functions of RANKL/RANK/OPG in bone modeling and bone remodeling. Arch Biochem Biophys. 2008 May 15; 473(2): 139–146.
- Sims NA1, Jenkins BJ, Nakamura A, Quinn JM, Li R, Gillespie MT, Ernst M, Robb L, Martin TJ. Interleukin-11 receptor signaling is required for normal bone remodeling.J Bone Miner Res. 2005 Jul;20(7):1093-102.
- Bozec A1, Zaiss MM. T Regulatory Cells in Bone Remodelling. Curr Osteoporos Rep. 2017 Jun;15(3):121-125.
- Mark C.HorowitzPhD. The Role of Cytokines in Bone Remodeling. Journal of Clinical Densitometry.