# Dysregulation of the Cant1/β-Catenin/TCF4–CHSY1 Axis Underpins Impaired ECM Biosynthesis in Skeletal Disorders

## TL;DR

This study reveals how a protein called Cant1 helps build healthy bones and cartilage by regulating a key signaling pathway.

## Contribution

The study identifies a new Cant1/β-Catenin/TCF4–CHSY1 signaling axis that regulates extracellular matrix biosynthesis in skeletal development.

## Key findings

- Cant1 stabilizes Wnt/β-Catenin, which activates the CHSY1 gene to produce ECM components like collagen and sugars.
- Reduced Cant1 and β-Catenin lead to lower levels of glycosaminoglycans and proteoglycans in cartilage.
- Dysfunction in the Cant1/β-Catenin/TCF4–CHSY1 axis is a core cause of skeletal disorders.

## Abstract

Mutations in a specific protein called calcium-activated nucleotidase 1 (Cant1) cause skeletal deformities, but the role of Cant1 in these deformities remains unclear. This study shows how Cant1 acts as a key regulator of bone and cartilage health. We found that Cant1 binds to and stabilizes a protein called Wnt/β-Catenin. Wnt/β-Catenin then enters the cell nucleus to activate specific genes. One of these genes, CHSY1, is turned on to produce building blocks such as collagen and sugars that form the extracellular matrix (ECM), which acts as the scaffolding of cartilage. When Cant1 and Wnt/β-Catenin expression are suppressed, there is a reduction in glycosaminoglycans (GAGs; mucopolysaccharides) and proteoglycans (like ACAN), which create a hydrated, gel-like matrix by binding with hyaluronan and link proteins to make cartilage resistant to compression. Additionally, there is a decrease in the α-1 chain of type II collagen (COL2α1), which forms the structural mesh or framework that gives tissue its tensile strength. In summary, we identified a conserved signaling pathway, the Cant1/β-Catenin/transcription factor 4 (TCF4)–CHSY1 axis, that regulates ECM homeostasis during skeletal development. Dysfunction of this pathway is a core cause of skeletal disorders. These findings not only provide mechanistic insights into human Cant1-related skeletal diseases but also highlight potential new targets for broad-spectrum therapies aimed at correcting deficiencies in ECM biosynthesis.