Matrix Vesicle‐Associated SMS2 as a Novel Mediator of Biomineralization

ABSTRACT

SGMS2 , a gene encoding plasma membrane‐resident sphingomyelin synthase 2, SMS2, has emerged as an important determinant of skeletal ossification. Heterozygous SGMS2 variants are associated with a broad spectrum of bone phenotypes, ranging from rickets‐like deformities in childhood to early‐onset osteoporosis, implicating SMS2 in mineralization while the underlying mechanisms are incompletely resolved. As SMS2 activity alters the balance of membrane lipids such as ceramide and sphingomyelin, the effects of SMS2 dysfunction on the skeleton are likely to be multifactorial and distributed across multiple cell types and subcellular compartments. Our recent work has identified SMS2 as a key component of growth plate‐derived matrix vesicles, nanoscale membrane‐bound particles released by skeletal cells that nucleate mineral deposition. Consistent with a functional role in this compartment, inhibition of SMS2 reduced the mineralization capacity of isolated matrix vesicles ex vivo . Collectively, these observations suggest that SMS2 contributes directly to biomineralization within matrix vesicles. Here, we place this emerging finding in the broader context of skeletal biology, disease mechanism, and therapeutic potential.