Heritable sclerosing bone disorders: presentation and new molecular mechanisms

Abstract

Sclerosing bone disorders can be subdivided according to their clinical presentation, the primarily affected cell type, and the cellular pathways. Osteoclast-rich osteopetrosis and related disorders have been related in most cases to mutations in genes required for osteoclast function. More recently, osteoclast-poor forms of osteopetrosis have been described as being connected to factors that govern osteoclast differentiation. However, increased bone formation can also cause osteosclerosis. Camurati-Engelman disease and osteopoikilosis are both related transforming growth factor-beta signaling. Rare recessive or dominant sclerosing disorders, such as endosteal hyperostosis, sclerosteosis, van Buchem disease, high bone-mass syndrome, and osteopathia striata, are caused by mutations in genes involved in the Wnt pathway, which regulates osteoblast differentiation. Finally, a third entity, including Ghosal syndrome and pachydermoperiostosis, is related to mutations in genes of the eicosanoid pathway. Clinical aspects and the consequences for our understanding of bone biology are discussed.