LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption

Abstract

Tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL) regulates multiple physiological or pathological functions, including osteoclast differentiation and osteoporosis. TNFRSF11A (also called RANK) is considered to be the sole receptor for RANKL. Herein we report that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. RANKL binding to LGR4 activates the Gαq and GSK3-β signaling pathway, an action that suppresses the expression and activity of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATC1) during osteoclastogenesis. Both whole-body (Lgr4(-/-)) and monocyte conditional knockout mice of Lgr4 (Lgr4 CKO) exhibit osteoclast hyperactivation (including elevation of osteoclast number, surface area, and size) and increased bone erosion. The soluble LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Moreover, LGR4-ECD therapeutically abrogated RANKL-induced bone loss in three mouse models of osteoporosis. Therefore, LGR4 acts as a second RANKL receptor that negatively regulates osteoclast differentiation and bone resorption.

RANKL coordinates multiple osteoclastogenic pathways by regulating expression of ubiquitin ligase RNF146

“…In a recent study, J. Luo et al demonstrated that leucine-rich repeat-containing G proteincoupled receptor 4 (LGR4) is a new receptor for RANKL (38). They showed that the RANKL/LGR4 signaling pathway inhibits the expression and activity of NFATc1 through activation of Gαq, leading to impairment of osteoclastogenesis, while Lgr4 −/− mice suffer from osteopenia due to activation of the osteoclast developmental program (38). These results indicate that RANKL provides a dichotomous signal mediated through 2 distinct receptor systems to control osteoclastogenesis.…”

LGRs receptors as peculiar GPCRs involved in cancer

“…Beside the Rspondin ligands, the Norrin protein belonging to the bone morphogenic protein antagonist family has also been described to bind the three LGR paralogues, but only interaction with LGR4 does stimulate the Wnt/β-catenin pathway (nevertheless independently of Wnt3a or Rspondins) [40] ( Figure 1A). In contrast, interaction of LGR4 with the RANKL ligand (also known as Tumor necrosis factor superfamily member 11-Tnfsf11) involves intracellular Gαq engagement leading to inhibition of RANKL-induced osteoclast activation and bone loss [41]. This suggests that LGR4 would act as a decoy receptor for RANKL, a function which can be suppressed by Rspondin1/Rspondin2 due to competitive partially overlapping binding of these two ligands to the LGR4 ECD ( Figure 1A).…”

“…This suggests that LGR4 would act as a decoy receptor for RANKL, a function which can be suppressed by Rspondin1/Rspondin2 due to competitive partially overlapping binding of these two ligands to the LGR4 ECD ( Figure 1A). Still, controversy remains regarding potential involvement of the Wnt/β-catenin in this process [41,42]. Another argument for LGR4 activity regardless of Wnt/β-catenin stimulation is the reported control of LGR4 in the white-to-brown fat switch in adipose tissues.…”

MECHANISMS IN ENDOCRINOLOGY: Genetics of human bone formation

“…Although, LGR4 is reported to be a receptor for R-spondins, which can modulate WNT signalling activity, in vitro and in vivo studies in knockout mice demonstrated that Lgr4 regulates osteoblast differentiation and mineralisation via another regulatory mechanism namely cAMP-PKAAft4 signalling (105). In addition, a recent study reported that Lgr4 negatively regulates osteoclast differentiation and bone resorption by interacting with RANKL (106).…”

“…Consequently, the reduced bone mass seen in the presence of the nonsense mutation in LGR4 and in the Lgr4-knockout mouse can not only be explained by a delay in osteoblast differentiation and mineralisation but also by an increased bone resorption (105,106). Investigation in other populations suggested that the variant is specific for the Icelandic population.…”