The primary cilium is an outward projecting antenna-like organelle with an important role in bone mechanotransduction. The capacity to sense mechanical stimuli can affect important cellular and molecular aspects of bone tissue. Idiopathic scoliosis (IS) is a complex pediatric disease of unknown cause, defined by abnormal spinal curvatures. We demonstrate significant elongation of primary cilia in IS patient bone cells. In response to mechanical stimulation, these IS cells differentially express osteogenic factors, mechanosensitive genes, and signaling genes. Considering that numerous ciliary genes are associated with a scoliosis phenotype, among ciliopathies and knockout animal models, we expected IS patients to have an accumulation of rare variants in ciliary genes. Instead, our SKAT-O analysis of whole exomes showed an enrichment among IS patients for rare variants in genes with a role in cellular mechanotransduction. Our data indicates defective cilia in IS bone cells, which may be linked to heterogeneous gene variants pertaining to cellular mechanotransduction.
Genetic approaches to complex diseases are subject to the currently available technological innovations, and successes or failures using these approaches influence our hypotheses for the genetic contributions to complex diseases. Common complex diseases with a genetic contribution result in the bulk of healthcare expenses through chronic care. It is thought that an understanding of the genetic contributions to common complex diseases will allow for advances in disease prevention, mitigation of disease pathogenesis and curative treatments. The authors discuss genetic approaches to complex diseases from the perspective of idiopathic scoliosis, a prevalent vertebral deformity syndrome that involves the integration of clinical, psychological, mechanical, and basic science disciplines. The authors focus specifically on the different hypotheses and approaches for genetic study, drawing on past studies and discussing possible future studies, with consideration of technological innovations. Key Concepts: The genetic basis of idiopathic scoliosis is not well understood. Idiopathic scoliosis is a complex deformity syndrome with a complex genetic component. Idiopathic scoliosis is the most common form of human spinal deformity. IS imposes a substantial healthcare cost through bracing, hospitalisations, surgery and chronic back pain. Identification of IS genes might lead to innovations in screening and treatment.
Adolescent idiopathic scoliosis (AIS) is the most prevalent pediatric spinal deformity. We previously demonstrated elongated cilia and an altered molecular mechanosensory response in AIS osteoblasts. The purpose of this exploratory study was to characterize the mechanosensory defect occurring in AIS osteoblasts. We found that cilia length dynamics in response to flow significantly differ in AIS osteoblasts compared to control cells. In addition, strain-induced rearrangement of actin filaments was compromised resulting in a failure of AIS osteoblasts to position or elongate in function of the bidirectional-applied flow. Contrary to control osteoblasts, fluid flow had an inhibitory effect on AIS cell migration. Moreover, flow induced an increase in secreted VEGF-A and PGE2 in control but not AIS cells. Collectively our data demonstrated that in addition to the observed primary cilium defects, there are cytoskeletal abnormalities correlated to impaired mechanotransduction in AIS. Thus, we propose that the AIS etiology could be a result of generalized defects in cellular mechanotransduction given that an adolescent growing spine is under constant stimulation for growth and bone remodeling in response to applied mechanical forces. Recognition of an altered mechanotransduction as part of the AIS pathomechanism must be considered in the conception and development of more effective bracing treatments.
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