The pathogenesis and intersecting mechanisms of monogenic bone mass disorders

Abstract

Monogenic disorders of bone mass arise from variants in single genes disrupting the intricate processes of bone formation and resorption. Genes underlying bone mass disorders are involved in various intersecting molecular mechanisms in cells of the mesenchymal and haematopoietic lineages. Signalling pathways, including WNT–β-catenin, TGFβ–BMP and NF-κB, have central roles in bone metabolism, and variants in their regulators or effectors can have opposing effects on bone mass. Defects in osteoblast differentiation, collagen biosynthesis and extracellular matrix mineralization primarily drive the pathogenesis of low bone mass (LBM) conditions, exemplified by various forms of osteogenesis imperfecta. Conversely, impaired osteoclast differentiation and function, or enhanced osteoblastic activity underlie high bone mass (HBM) disorders, such as osteopetrosis and osteosclerosis. A subset of genes have pleiotropic effects, contributing to both LBM and HBM disorders depending on the genetic background. Advances in genetics have not only elucidated pathogenic mechanisms, but also enabled the development of targeted therapies, including anti-sclerostin antibodies and enzyme replacement therapies. However, most LBM and HBM conditions still have no cure. Understanding the shared and divergent mechanisms of bone mass regulation will offer insights into future therapeutic strategies. Advances in gene discovery, disease classification and targeted therapies are rapidly reshaping our understanding of monogenic disorders of low and high bone mass. In this Review, Padidela and colleagues discuss the intersecting molecular mechanisms within mesenchymal and haematopoietic cell lineages that disrupt the intricate processes of bone formation and resorption, causing these phenotypes.