Rankl

RANKL was discovered in 1997 by four independent working groups. Two of them described the role of RANKL in osteoclast differentiation (Lacey et al. 1998/ Yasuda et al. 1998), whereas two other research groups demonstrated the expression of RANKL on the surface of activated T cells and dendritic cells (Anderson et al. 1997/ Wong et al. 1997).

RANKL is the acronym for "Receptor Activator of NF-κB Ligand". RANKL is mainly expressed and secreted by osteoblasts. The protein belongs to the family of tumor necrosis factors. RANKL is the only known ligand of RANK (Owen et al. 2013), a transmembrane receptor protein that is expressed by monocytic osteoclast precursor cells (preosteoclasts), among others. These are derived from the same hematopoietic stem cell as the monocytes.

The intracellular signaling pathway after binding of its ligand to RANK is complex. Receptor binding causes receptor trimerization with subsequent recruitment of adapter molecules such as CSRC and TNF receptor-associated factor 6 (TRAF6). Receptor binding and activation leads to the differentiation of preosteoclasts into osteoclasts.

The RANK/RANKL system is a central biological control system. It ensures that bone resorption and bone formation remain in a physiological balance. This equilibration is a prerequisite for the formation and normal architecture of the bone system. This balance is disturbed in various diseases.

RANKL can be antagonized by osteoprotegerin (OPG). Osteoprotegerin (OPG) is a secreted variant of RANK and is also secreted by osteoblasts. Osteoprotegerin binds the ligand RANKL but does not induce signal transduction, so that the activity of osteoclasts is inhibited. Thus, by producing osteoprotegerin, the osteoblasts counteract osteoclast differentiation via the RANKL pathway itself.

Through interaction with RANKL, RANK regulates cell proliferation as well as cell differentiation. Furthermore, RANK could be detected on the surface of dendritic cells, where it has an anti-apoptotic effect. However, the more precise (immunological) functions have not yet been sufficiently clarified (Hanada et al., 2011; Hofbauer, 2010).

Influence of the calcium level on RAKL/RANK: If the serum calcium level drops, the parathyroid gland releases increased amounts of parathyroid hormone (PTH). This cannot have a direct effect on the osteoclasts because they do not have a suitable PTH receptor. The parathormone acts on the osteoblasts, which are stimulated to produce RANKL. The increased differentiation and activity of the osteoclasts leads to increased resorption and thus to an increase in the calcium level.

Influence of estrogens: Estrogens act as physiological suppressors of RANKL. This explains the frequency of osteoporosis in postmenopausal women, since the natural suppressor of osteoclast differentiation (estrogen) is no longer present in sufficient quantities.

Other:

• Dysregulation of RANK/RANKL interactions is found in a wide variety of clinical pictures which are associated with a reduction in bone density due to chronic excessive T-cell activation, including Crohn's disease (MC).
• RANKL is also expressed in various tumors such as breast, gastric, renal cell carcinoma and extramammary Paget's disease (Owen S et al. 2013, Kambayashi Y et al. 2018). The biological significance of these expressions has not yet been clearly clarified (Owen S et al. 2013), but is associated with a worse prognosis (Steven A et al. 2018). RANKL can be secreted by various tumour cells in an unregulated manner, which causes tumour-related increased bone resorption.

The deciphering of the RANK/RANKL/OPG pathway has been a pioneering step in the development of a clinically applicable RANKL inhibitor: Denosumab, a human IgG2 anti-RANKL monoclonal antibody (see monoclonal antibodies below) that mimics the effects of OPG. In contrast to osteoprotegerin (OPG), Denosumab is highly selective, i.e. the antibody does not bind to other members of the TNF family and thus enables specific inhibition of RANKL activity.

Another new RANKL receptor described, the Leucinerich repeat-containing G-protein-coupled receptor 4 (LGR4), appears to compete with RANK and suppress the canonical RANK signaling pathway during osteoclast differentiation (Luo et al. 2016).

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11. Zhang X et al. (2017) RANKL/RANK pathway abrogates cetuximab sensitivity in gastric cancer cells via activation of EGFR and c-Src. OncoTargets and Therapy 10: 73-83.