LGR4, a G Protein-Coupled Receptor With a Systemic Role: From Development to Metabolic Regulation

Abstract

Leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4/GPR48), a member of the GPCR (G protein-coupled receptors) superfamily, subfamily B, is a common intestinal crypt stem cell marker. It binds R-spondins/Norrin as classical ligands and plays a crucial role in Wnt signaling potentiation. Interaction between LGR4 and R-spondins initiates many Wnt-driven developmental processes, e.g., kidney, eye, or reproductive tract formation, as well as intestinal crypt (Paneth) stem cell pool maintenance. Besides the well-described role of LGR4 in development, several novel functions of this receptor have recently been discovered. In this context, LGR4 was indicated to participate in TGFβ and NFκB signaling regulation in hematopoietic precursors and intestinal cells, respectively, and found to be a new, alternative receptor for RANKL (Receptor Activator of NF kappa B Ligand) in bone cells. LGR4 inhibits the process of osteoclast differentiation, by antagonizing the interaction between RANK (Receptor Activator of NF kappa B) and its ligand-RANKL. It is also known to trigger anti-inflammatory responses in different tissues (liver, intestine, cardiac cells, and skin), serve as a sensor of the circadian clock in the liver, regulate adipogenesis and energy expenditure in adipose tissue and skeletal muscles, respectively. The extracellular domain of LGR4 (LGR4-ECD) has emerged as a potential new therapeutic for osteoporosis and cancer. LGR4 integrates different signaling pathways and regulates various cellular processes vital for maintaining whole-body homeostasis. Yet, the role of LGR4 in many cell types (e.g. pancreatic beta cells) and diseases (e.g., diabetes) remains to be elucidated. Considering the broad spectrum of LGR4 actions, this review aims to discuss both canonical and novel roles of LGR4, with emphasis on emerging research directions focused on this receptor.

BMP9 induces osteogenic differentiation through up-regulating LGR4 via the mTORC1/Stat3 pathway in mesenchymal stem cells

“… 49 Several studies have highlighted the significant role of LGR4, a crucial Wnt/β-catenin regulator, in regulating BMSC differentiation as well as bone development and homeostasis. 19 , 50 Abnormal LGR4 expression was observed in a variety of bone loss diseases. 16 LGR4 -KO mice have been found to exhibit delayed osteogenic differentiation and mineralization.…”

Alternative Polyadenylation Results in mRNA Transcript Instability in Gestational Diabetes Mellitus

“…LGR4 also plays an important role in metabolic regulation, coordinating various metabolic signals. 21 Recently, Dong et al 22,23 described RSPO2/LGR4 as a key regulator for the differentiation of precursor cells into adipocytes. In addition, Li et al observed that the level of LGR4 in diabetes patients was significantly lower than that in non-diabetes patients (P<0.05), and the level of LGR4 in hypertensive patients was lower than that in non-hypertensive patients with higher blood pressure.…”

Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis

“…It also regulates OB differentiation in vivo and in vitro ( Luo et al, 2009 ). LGR4 is also present in different tissues and consequently it has been linked with systemic roles from development to metabolic regulation ( Filipowska et al, 2022 ).…”

“…PTH appears to increase the amount of OB precursors in the bone marrow through a direct action. The bone marrow cells capable of differentiating to OBs are the colony-forming units-fibroblast (CFU-F) and old studies already demonstrated that the administration of PTH ( Kalantar-Zadeh et al, 2021 ; Csaba, 2022 ; Alberto Ortiz, 2022 ; Elshahat et al, 2020 ; Moe et al, 2006 ; Kidney Disease: Improving Global Outcomes KDIGO CKD-MBD Update Work Group, 2017 ; Wang et al, 2018 ; Kidney Disease: Improving Global Outcomes KDIGOCKD–MBD Work Group, 2009 ; Vervloet et al, 2014 ; Torregrosa et al, 2022 ; Llach et al, 2000 ; Lucas, 1883 ; Hruska et al, 2017 ; Goltzman et al, 2018 ; Day et al, 2005 ; Takada et al, 2007 ; Guo et al, 2010 ; Vasikaran et al, 2011 ; Tridimas et al, 2021 ; Bover et al, 2021a ; Bover et al, 2018 ; Bover et al, 2021b ; Wada et al, 2006 ; Gori et al, 2000 ; Luo et al, 2016 ; Luo et al, 2009 ; Filipowska et al, 2022 ; Luxenburg et al, 2007 ; Wheater et al, 2013 ; Rochefort et al, 2010 ; Orlando, 2020 ; Richter and Faul, 2018 ; Vervloet, 2020 ; Gutiérrez et al, 2008 ) to rats for 1 week resulted in the doubling of CFU-F compared with placebo-treated rats ( Nishida et al, 1994 ).…”