Loss of CSF-contacting neuron sensory function is associated with a hyper-kyphosis of the spine reminiscent of Scheuermann’s disease

Abstract

Scheuermann’s disease, also referred to as Scheuermann’s kyphosis, is the second most frequent spine deformity occurring in humans after adolescent idiopathic scoliosis (AIS), both with an unclear etiology. Recent genetic studies in zebrafish unraveled new mechanisms linked to AIS, highlighting the role of the Reissner fiber, an acellular polymer bathing in the cerebrospinal fluid (CSF) in close proximity with ciliated cells and mechanosensory neurons lining the central canal of the spinal cord (CSF-cNs). However, while the Reissner fiber and ciliary beating have been linked to AIS-like phenotypes in zebrafish, the relevance of the sensory functions of CSF-cNs for human spine disorders remains unknown. Here, we show that the thoracic hyper-kyphosis of the spine previously reported in adult pkd2l1 mutant zebrafish, in which the mechanosensory function of CSF-cNs is likely defective, is restricted to the sagittal plane and is not associated with vertebral malformations. By applying orthopedic criteria to analyze the amplitude of the curvature at the apex of the kyphosis, the curve pattern, the sagittal balance and sex bias, we demonstrate that pkd2l1 knock-outs develop a phenotype reminiscent of Scheuermann’s disease. Altogether our work consolidates the benefit of combining genetics and analysis of spine deformities in zebrafish to model idiopathic spine disorders in humans.

Doença de Scheuermann: uma abordagem diagnóstica, evolução clínica e revisão

“…Os efeitos a longo prazo da hipercifose podem incluir lombalgia crônica, perda do equilíbrio, aumento no risco de quedas e fraturas devido às alterações mecânicas da coluna, independentemente da densidade mineral óssea. Mulheres em idade avançada com hipercifose tem risco aumentado para fraturas de vértebras e periféricos, muitas vezes, devido a degeneração do disco e perda da altura do disco, produzindo tensão de tração na placa terminal aumentando o risco de falha da vértebra com troncos e pernas mais rígidas, impossibilitando um tempo de reação adequado durante a queda 7 .…”

The significance of cerebrospinal fluid dynamics in adolescent idiopathic scoliosis using time-SLIP MRI

“…While the exact etiology of AIS remains elusive, it represents a multifactorial disease with genetic, neuromuscular, biomechanical, and other factors implicated in its onset and progression 2 . One area of intrigue within this multifaceted disease panorama has been the potential role of cerebrospinal fluid (CSF) dynamics in AIS patients 3 – 5 . The CSF, encasing the brain and spinal cord, plays a pivotal role in supporting neural structures, providing nutrients, and clearing metabolic waste 3 , 4 .…”

“…One area of intrigue within this multifaceted disease panorama has been the potential role of cerebrospinal fluid (CSF) dynamics in AIS patients 3 – 5 . The CSF, encasing the brain and spinal cord, plays a pivotal role in supporting neural structures, providing nutrients, and clearing metabolic waste 3 , 4 . Any perturbations in its flow dynamics could potentially influence the surrounding neural and osseous tissues, including the vertebral column.…”

“…While zebrafish models provide initial insights into CSF dynamics and scoliosis, it is critical to consider the scale-dependent nature of fluid hydrodynamics when extrapolating these findings to humans. Several prior human studies have explored this connection, using modalities like contrast MRI 3 , 5 , 7 , 8 . These studies, along with certain animal models, have laid the groundwork suggesting that alterations in CSF dynamics might be linked to the development or progression of scoliosis.…”

“…However, while promising, the usage of contrast MRI presents certain challenges. Not only is it invasive, posing potential risks to patients, but the labelling time of CSF during the study is inherently limited 3 , 5 , 7 , 8 . This confines our understanding and ability to capture the complete picture of CSF dynamics over extended durations.…”