Review
Role of RANKL in bone diseases

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Bone remodeling is a tightly regulated process of osteoclast-mediated bone resorption, balanced by osteoblast-mediated bone formation. Disruption of this balance can lead to increased bone turnover, resulting in excessive bone loss or extra bone formation and consequent skeletal disease. The receptor activator of nuclear factor κB ligand (RANKL) (along with its receptor), the receptor activator of nuclear factor κB and its natural decoy receptor, osteoprotegerin, are the final effector proteins of osteoclastic bone resorption. Here, I provide an overview of recent studies that highlight the key role of RANKL in the pathophysiology of several bone diseases and discuss the novel therapeutic approaches afforded by the modulation of RANKL.

Section snippets

Bone remodeling

Bone remodeling is a continuous process that helps repair the micro damage of bone matrix and adjust bone architecture to maintain bone strength. In this tightly regulated process, the amount of bone resorbed is matched by the amount of newly formed bone. Osteoclasts, multinucleated cells derived from the myeloid hempoietic lineage, are the principal cells involved in bone resorption, whereas osteoblasts, cells that originate from the multipotent mesenchymal stem cells, carry out the bone

The RANKL protein

RANKL is a member of the tumor necrosis factor (TNF) super family, the locus for which has been traced to the 13q14 human chromosome [1]. It is produced as a 317 amino acid and exists as either a membrane-bound protein or can be cleaved to form a secreted protein that still retains activity [2]. RANKL is highly expressed in peripheral lymph nodes and bone marrow, thymus, spleen, Peyer's patches, brain, heart, skin, skeletal muscle, kidney, liver, lung and mammary tissue 3, 4. Cells that produce

RANKL signaling pathway

The recognition that the interaction of RANKL and RANK is a key step in the activation of osteoclasts was followed by attempts to unravel the molecular mechanisms that follow this initial step. Recent studies have helped identify the important players of this signal transduction pathway (Figure 1). Binding of RANKL to RANK is followed by recruitment of the TNF receptor-associated factor (TRAF). Although several of these proteins, TRAFs 1, 2, 3, 5 and 6, are involved in the RANK signaling

Role of RANKL in normal bone remodeling

RANKL has an important role at various stages of osteoclast differentiation and function. The fusion of osteoclast precursors to form multinucleated cells, their differentiation into mature osteoclasts and the attachment of osteoclasts to bone and activation to resorb bone are all influenced by RANKL [3]. RANKL also inhibits osteoclast apoptosis and thereby leads to continued survival of these cells [17]. The predominant role of RANKL in osteoclastogenesis was demonstrated in genetic knockout

Role of RANKL in pathological states of bone remodeling

An imbalance in the RANKL:OPG ratio that results in increased RANKL levels leads to increased osteoclastogenesis and consequently to an increase in bone loss. This imbalance is the basis of several bone diseases characterized by bone loss that might manifest as either systemic or localized bone loss. Here, I review the role of RANKL in these various bone diseases.

Role of RANKL in other diseases

Recent studies have highlighted the role of RANKL in the pathogenesis of several other diseases. For example, the role of the RANKL/OPG system in bone remodeling indicates that there is also a role for this system in fracture healing. It is speculated that RANKL has a role in callus formation but might not have an influence on biomechanical strength of new bone [47]. Support to the previously mentioned hypothesis was provided by a study in which treatment with RANK-Fc was shown to eliminate

RANKL inhibition

The knowledge that RANKL has a crucial role in the pathogenesis of bone loss, along with the realization that the RANKL/RANK/OPG pathway is the final effector pathway of osteoclastic bone resorption, has led to the development of novel therapeutic agents that target this pathway (Box 2). Initial studies utilized the natural decoy OPG for this purpose. Preclinical studies showed that inhibition of RANKL with OPG led to an increase in bone density and bone strength 52, 53. These studies were

Conclusion

The discovery of the RANKL/RANK/OPG system has helped bring together studies of bone biology and immunology and create the new field of osteoimmunology. Studies over the past decade have highlighted the pivotal role played by RANKL in post-menopausal osteoporosis, inflammatory arthritides, metastatic bone tumors and other bone diseases associated with increased bone loss. Recent studies have identified the proteins involved in the RANKL signaling pathway. Furthermore, scientists have elucidated

Glossary

Ankylosing spondylitis
a chronic, painful, inflammatory arthritis primarily of the spine and sacroiliac joints.
Aseptic loosening of joint replacement
a disabling condition that occurs 5-10 years after joint replacement surgery, characterized by increased bone resorption around the prosthetic joint that results in loosening of the prosthetic joint.
Bone erosions
an area of focal bone loss with evidence for a cortical break on imaging.
Bone mineral density
bone mass measurement; the assessment of the

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