Abstract
ABSTRACTLeucine‐rich repeat‐containing G protein‐coupled receptors (LGRs) are adult stem cell markers that have been described across various stem cell niches, and expression of LGRs and their corresponding ligands (R‐spondins) has now been reported in multiple bone‐specific cell types. The skeleton harbors elusive somatic stem cell populations that are exceedingly compartment‐specific and under tight regulation from various signaling pathways. Skeletal progenitors give rise to multiple tissues during development and during regenerative processes of bone, requiring postnatal endochondral and intramembranous ossification. The relevance of LGRs and the LGR/R‐spondin ligand interaction in bone and tooth biology is becoming increasingly appreciated. LGRs may define specific stem cell and progenitor populations and their behavior during both development and regeneration, and their role as Wnt‐associated receptors with specific ligands poses these proteins as unique therapeutic targets via potential R‐spondin agonism. This review seeks to outline the current literature on LGRs in the context of bone and its associated tissues, and points to key future directions for studying the functional role of LGRs and ligands in skeletal biology. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
Leucine-rich repeat-containing G protein-coupled receptors (LGRs) are a family of adult stem cell surface proteins that have been studied in organs with well-defined stem cell niches, including the hair follicle and intestine.[1,2] The LGR family members (LGR4/5/6) mark distinct cells with specialized functions during homeostasis and stress responses, mainly in Wnt-driven progenitor compartments,(3,4) and play a critical role in defining progenitor and stem cell behavior.[2,5]Skeletal stem cells are required for bone formation during development, for proper differentiation of functional osteoblasts during homeostatic bone remodeling, and for providing osteochondral progenitors during postnatal regenerative processes
LGRs are G protein-coupled receptors belonging to a class A rhodopsin-like family.[15]. They are a conserved group of 7-transmembrane proteins with characteristic leucine-rich repeats in the N-terminal extracellular domain that can mediate ligand interaction.[16–18] A family of secreted proteins called RSpondins (RSPOs) have been identified as ligands for LGRs,(19–23) where all mammalian R-spondins (RSPO1–4) share a similar protein structure with two furin-like repeat domains that act as the binding domain for the receptors (Fig. 1).(22,24) each of the LGRs have a similar and highly conserved structure, LGR4 and LGR5 feature 17 leucine-rich repeats, whereas LGR6 contains 13 repeats.[16]. Despite the fact that LGRs constitute a subfamily within the G protein-coupled receptor (GPCR) superfamily,(25)
RSPO2 promotes osteoblast formation and activates canonical Wnt signaling in a MC3T3-E1 preosteoblast cell line, an effect that is abrogated upon siRNAinduced knockdown of LGR4(68); RSPO2 has been shown to induce bone formation in vivo, studies to determine receptor activation during this process are needed.[69]. Further, bone marrow-derived mesenchymal stem cells (MSCs) isolated from LGR4-KO mice show reduced osteoblastic differentiation.[62]. Zhang and colleagues report a LGR4-mediated
Summary
Leucine-rich repeat-containing G protein-coupled receptors (LGRs) are a family of adult stem cell surface proteins that have been studied in organs with well-defined stem cell niches, including the hair follicle and intestine.[1,2] The LGR family members (LGR4/5/6) mark distinct cells with specialized functions during homeostasis and stress responses, mainly in Wnt-driven progenitor compartments,(3,4) and play a critical role in defining progenitor and stem cell behavior.[2,5]Skeletal stem cells are required for bone formation during development, for proper differentiation of functional osteoblasts during homeostatic bone remodeling, and for providing osteochondral progenitors during postnatal regenerative processes.
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