Khavandgar et al. demonstrate that bone-forming osteoblasts require the enzyme neutral sphingomyelinase 2 (nSMase2) to mineralize the extracellular matrix during skeletal development.
nSMase2 cleaves sphingomyelin to generate ceramide and other bioactive lipids. Mice lacking nSMase2 have severe skeletal abnormalities such as shortened and bent limb bones. The precise nature of these skeletal defects has remained unclear, however, as has the site of nSMase2’s action. Some studies have suggested that nSMase2 acts in the brain to regulate endocrine signals controlling bone development.
Khavandgar et al. analyzed mice lacking nSMase2 activity due to a chemically induced mutation called fragilitas ossium (fro) and found that although their osteoblasts differentiated and secreted collagen matrix as normal, they failed to mineralize this matrix with calcium and inorganic phosphate. Mutant osteoblasts also failed to mineralize in culture. In addition, the long bones of fro/fro embryos contained increased numbers of hypertrophic chondrocyte-like cells that normally die during long bone growth. Restoring wild-type nSMase2 expression to the osteoblasts of fro/fro mice rescued the bone mineralization and skeletal defects of these animals. Osteoblast-specific nSMase2 expression failed to boost hypertrophic chondrocyte apoptosis, however, indicating that nSMase2 has tissue-specific functions during skeletal development.
The results may explain why some osteogenesis imperfecta patients have bone mineralization defects despite having intact collagen genes and normal levels of mineral ions in their serum. Senior author Monzur Murshed now wants to investigate how nSMase2 promotes mineralization. The enzyme may regulate the release of specialized matrix vesicles from osteoblasts that initiate the mineralization process.