Paget Disease of Bone : Pathogenesis

Comments:
Pathogenesis of Paget Disease of Bone (PDB): PDB is characterized by disruption of normal cycle of bone remodeling in one or more bones leading to a disordered bone architecture. One of the key mechanisms is dysregulation of osteoclast differentiation and function. The main steps in osteoclast differentiation pathway are shown in this illustration.

Genetic factors play a key role in the pathogenesis of PDB. About 10-20% of PDB cases are familial and show an autosomal dominant pattern with incomplete penetrance. Several closely related genes that regulate osteoclast differentiation and function are involved. The risk of developing PDB appears to depend upon rare, high-penetrance mutations in genes such as SQSTM1 in conjunction with common mutations in genes such as CSF1, TNFRSF11A, and TM7SF4.

The most well-studied is Sequestosome 1 gene (SQSTM1) on chromosome 5q35.3 which encodes p62 - a protein that plays a key role in regulating osteoclast activity via NF-κB signaling pathway (see next image). Mutations in SQSTM1 causing osteoclastic overactivity have been found in 50% of familial cases and 5-10% of sporadic cases of PDB.

Abbreviations: M-CSF= macrophage colony stimulating factor; RANK receptor activator of nuclear factor-kappa B; RANKL = RANK ligand; OPG = osteoprotegerin; VCP = valosin contain protein; OPTN = optineurin

Credit: Illustration created with BioRender.com