Comprehensive analysis of the skeletal phenotype in Chst14-/- mice: implications for dermatan sulfate in bone structure and strength.

Dermatan sulfate (DS) is a glycosaminoglycan known to contribute to tissue strength through collagen fibril assembly. Musculocontractural Ehlers-Danlos syndrome (mcEDS) caused by pathogenic variants in the gene that encodes carbohydrate sulfotransferase 14 (CHST14) (mcEDS-CHST14) is a representative disorder of DS deficiency. Skeletal lesions, such as progressive spinal deformity and osteoporosis/osteopenia, are significant manifestations of mcEDS-CHST14, which can lead to deterioration in quality of life. To characterize skeletal alterations associated with DS deficiency, we performed comprehensive analyses of the skeletal phenotypes in Chst14 gene-deleted (Chst14-/-) mice. Chst14-/- mice exhibited progressive kyphosis, proximal femoral deformities, and decreased bone strength, as well as reduced trabecular bone mass and structural parameters, from a young age. Qualitative ultrastructural alterations of collagen fibrils in cortical bone were observed in middle-aged Chst14-/- mice by transmission electron microscopy. In addition, cortical bone showed increased expression of receptor activator of NF-κB (Rank), a gene involved in osteoclast differentiation, in middle age. Histomorphometric analyses of cancellous bone demonstrated reduced trabecular structural parameters in Chst14-/- mice, including decreases in bone volume and trabecular number. These findings indicate age-dependent alterations in both cortical and cancellous bone compartments that may contribute to progressive skeletal deformation. The present study provides insight into skeletal alterations associated with mcEDS-CHST14 and highlights a broader role of DS in maintaining bone structure and strength.