An adhesion G protein-coupled receptor is required in cartilaginous and dense connective tissues to maintain spine alignment.

Zhaoyang Liu,Jess G Snedeker,Yunjia Wang,Amro A Hussien,Roberto Gonzalez,Courtney M Karner,Ryan S Gray,Terry Heckmann

doi:10.7554/elife.67781

Abstract

Adolescent idiopathic scoliosis (AIS) is the most common spine disorder affecting children worldwide, yet little is known about the pathogenesis of this disorder. Here, we demonstrate that genetic regulation of structural components of the axial skeleton, the intervertebral discs, and dense connective tissues (i.e., ligaments and tendons) is essential for the maintenance of spinal alignment. We show that the adhesion G protein-coupled receptor ADGRG6, previously implicated in human AIS association studies, is required in these tissues to maintain typical spine alignment in mice. Furthermore, we show that ADGRG6 regulates biomechanical properties of tendon and stimulates CREB signaling governing gene expression in cartilaginous tissues of the spine. Treatment with a cAMP agonist could mirror aspects of receptor function in culture, thus defining core pathways for regulating these axial cartilaginous and connective tissues. As ADGRG6 is a key gene involved in human AIS, these findings open up novel therapeutic opportunities for human scoliosis.

Highlights

The maturation and homeostasis of a healthy, functional spine require the integration of several musculoskeletal tissues, including bone, cartilage, and connective tissues, muscle, and the peripheral nervous system
Adgrg6/ADGRG6 is expressed in the intervertebral disc and supraspinous ligaments
GPR126/ADGRG6 locus are associated with Adolescent idiopathic scoliosis (AIS) in humans (Kou et al, 2013; Kou et al, 2018)

Summary

Introduction

The maturation and homeostasis of a healthy, functional spine require the integration of several musculoskeletal tissues, including bone, cartilage, and connective tissues, muscle, and the peripheral nervous system. The spine consists of a series of segmented bony vertebral bodies linked together by fibrocartilaginous joints named the intervertebral discs (IVDs), which aid in lateral and rotational flexibility and cushioning loading of the spinal column. The structural organization of the axial skeleton aids in the protection of the spinal cord and acts as the central axis of the body to support and maintain posture during movement through the environment (Bagnat and Gray, 2020; Bogduk, 2016). Scoliosis can be caused by congenital patterning defects of the vertebral column or associated with various neuromuscular or syndromic disorders (Murphy and Mooney, 2019). Idiopathic scoliosis occurs in otherwise healthy children without associated patterning or neuromuscular conditions. Adolescent idiopathic scoliosis (AIS) is the most common pediatric spine disorder, affecting ~3% of children worldwide (Cheng et al, 2015). Despite substantial efforts to decipher the pathogenesis of AIS, the molecular genetics and pathology underlying this condition remain ill-defined (Cheng et al, 2015; Newton Ede and Jones, 2016)

Results

Discussion

Conclusion