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Bone remodeling process and steps

The bone remodeling process is crucial for balancing the metabolic changes between bone formation and bone resorption.

Bone remodeling is carried out by two specialized cells, such as osteoblast and osteoclast.

The cell, osteoblast, is involved in both bone formation (ossification) and osteoclast production (osteoclastogenesis), while osteoclast plays a major role in bone resorption (break down).

The activation of these cells secures skeletal integrity and maintains blood mineral homeostasis throughout the organism’s life. However, any alterations in the remodeling of bone lead to bone disorders.

Image: Bone Remodelling Process/Mechanism

 The main factors involved in the bone remodeling process

1. Receptor activator of NFkB ligand (RANKL)

  • RANKL is a protein-ligand molecule (TNF-family cytokine) which express on the membrane of osteoblast cells.
  • The ligand is essential for osteoclast formation as well as for mammary gland and immune cell development.
  • RANKL is available in two forms in the cell, such as membrane-bound form or soluble form.
  • Both of these forms deliver signals for the formation of osteoclast cells.
  • In the osteoclast formation, RANKL will bind to its receptor, RANK (Nuclear factor-kB), and stimulate both the proliferation and differentiation of osteoclast progenitor cells.

2. RANK role in the bone remodeling process

  • The receptor activator of NF-κB is a receptor expressed on the membrane of osteoclast progenitor cells.
  • When it interacts with  RANKL, then that relays the signaling messages to intracellular transcription factors to induce the proliferation and differentiation of osteoclasts.

3. Osteoprotegerin for the remodeling of bone

  • Osteoprotegerin (OPG) is a cytokine receptor of the tumor necrosis factor receptor superfamily 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 is also called an 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 receptor.
  • Thus, the relative expressions of RANKL and OPG in bones are major determinants for bone mass and bone strength maintenance.
  • More concentrations of PGP than the concentration of RANKL reduce the activity of osteoclasts, thereby reducing the remodeling of bone.

4. Macrophage colony-stimulating factor (MCSF) and its function in the remodeling of bone 

  • MCSF is an essential factor involved in the remodeling of bone.
  • MCSF is important for the proliferation and differentiation of osteoclasts and monocytes and is involved in the tissue macrophages.
  • MCSF also plays a major role in the production and function of lysosomes and the formation of the ruffled border in osteoclast cells.
  • Ruffled borders are crucial for increasing the surface area of osteoclast cells to facilitate the delivery of digestive enzymes and the formation of an acidic environment to allow osteoclast for bone degradation.
  • The lysosome is found to be an important cellular organelle in osteoclast cells to digest engulfed bone fragments.
  • Deficiency of MCSF in the bone tissue results in abnormal bone formation.

5. c-Fms (M-CSF receptor) and its function in the remodeling of bone

  • c-Fms is a receptor found on the membrane of osteoclast progenitor cells and that allows the binding of  M-CSF ligand for tissue macrophages and proliferation of osteoclasts and monocytes.

6. Interleukins and their role in the remodeling of bone

  • Interleukins are cytokines, which are important mediators in the cellular signaling process.
  • In the case of bone remodeling, interleukins are produced by T-cells to activate osteoblast cells, which in turn release the signaling molecule to facilitate osteoclast proliferation and differentiation.

7. Serine-threonine protein kinase Akt role in the remodeling of bone

  • Both bone mass and its 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 factors in the signaling process mediated by bone anabolic factors.
  • Lower levels of Akt expression in osteoblasts and osteoclasts lead to low turnover of osteopenia due to dysfunctions of bone cells.
  • Akt was recognized as a crucial modulator for osteoblasts and osteoclasts for promoting their proliferation, differentiation, and survival to maintain bone mass and turnover.

Research on RANKL

  • In previous studies, scientists from the University of Arkansas for Medical Sciences, USA, performed experiments on RANKL (membrane-bound and soluble form) and stated that RANKL is an important factor in osteoclast formation.
  • For their studies, they generated mice, which have a sheddase-resistant enzyme (a protease enzyme that shows potent RANKL sheddase activity) for RANKL release.
  • Thus, this mouse lacks a soluble RANKL in its blood circulation.
  • From their experiments on mice, they found that deficiency of soluble RANKL affects the bone structure or its mass in mice but reduces osteoclast cell number and increases cancellous bone mass in adult mice.
  • They stated that the bone loss caused by estrogen deficiency, however, is unaffected by the absence of the soluble form of RANKL.
  • While, the 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 the physiological process of bone remodeling in adult mice.

References

  1. Brendan F. Boyce, M.D. and Lianping Xing, M.D., Ph.D. Functions of RANKL/RANK/OPG in bone modeling and bone remodelling. Arch Biochem Biophys. 2008 May 15; 473(2): 139–146.
  2. 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.
  3. Bozec A1, Zaiss MM. T Regulatory Cells in Bone Remodelling. Curr Osteoporos Rep. 2017 Jun;15(3):121-125.
  4. Mark C.HorowitzPhD. The Role of Cytokines in Bone Remodelling. Journal of Clinical Densitometry.
  5.  Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss. Nature Communications volume 9, Article number: 2909 (2018).