LGRs in Skeletal Tissues: An Emerging Role for Wnt‐Associated Adult Stem Cell Markers in Bone

Abstract

Leucine-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 bonespecific 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.

A spatial multi-omics atlas of the human lung reveals a novel immune cell survival niche

“…The cell type was located around the chondrocytes within cartilage in our Visium ST (Figure 2g) and could be identified by the expression of the marker gene COL12A1 in the human protein atlas (Figure S5c). Among the marker genes for PC-fibro, we detected bone development genes LGR4 and LGR6 (Doherty and Sanjay 2020) (Figure S5b). PC-fibro, which express standard fibroblasts markers, is unique in expressing genes relevant for bone development, placing these cells into a trajectory from adventitial fibroblasts to chondrocytes (Figure S5 d, e).…”

Wnt Pathway Extracellular Components and Their Essential Roles in Bone Homeostasis

“…These receptors bind to R-spondins (RSPOs), causing the formation of the LGR-RSPO-ZNRF/RNF43 complex. This leads to the sequestration of ZNF/RNF43, which causes an increase in membrane-available FDZs, since the transmembrane ubiquitin ligases ZNF/RNF43 are responsible for degrading them [ 31 ]. In addition to this agonistic effect on the Wnt pathway, LGR is a target gene of the Wnt pathway, which will produce a positive feedback loop [ 31 ].…”

“…This leads to the sequestration of ZNF/RNF43, which causes an increase in membrane-available FDZs, since the transmembrane ubiquitin ligases ZNF/RNF43 are responsible for degrading them [ 31 ]. In addition to this agonistic effect on the Wnt pathway, LGR is a target gene of the Wnt pathway, which will produce a positive feedback loop [ 31 ]. It has also been reported that LGR proteins mark different adult stem cells and play a very important role in defining progenitor and stem cell behavior [ 31 , 181 , 182 ].…”

“…In addition to this agonistic effect on the Wnt pathway, LGR is a target gene of the Wnt pathway, which will produce a positive feedback loop [ 31 ]. It has also been reported that LGR proteins mark different adult stem cells and play a very important role in defining progenitor and stem cell behavior [ 31 , 181 , 182 ]. Specifically, it has been reported that LGR5 is a marker of adult stem cells in the stomach [ 183 ], hair follicles [ 184 ] and small intestine and colon [ 181 ], among others, and LGR6 in the taste buds, lungs and skin [ 115 , 181 , 183 , 185 ].…”

“…Increased intracellular calcium can also activate calcineurin and CaMKII, which in turn can induce the activation of the NFAT transcription factor or NF-kB [ 26 , 30 ]. WNT signaling modulators: The binding of RSPO to LGR and to RNF43/ZNRF3 maintains the Wnt signal ON by preventing the polyubiquitination and endocytosis of FZD performed by RNF43/ZNF3 [ 31 ]. WNT production: Wnt precursors undergo post-translational modifications such as porcupine-mediated palmitoylation, other lipid modifications and glycosylation in the ER.…”