Figure 1.

Schematic representation of genes involved in osteoclast-poor and osteoclast-rich osteopetrosis. In red are indicated genes involved in the pathogenesis of ARO. MCSF and RANKL, cytokines secreted by osteoblasts and osteocytes, are necessary for the differentiation of osteoclast precursors into mature and resorbing osteoclasts. When these signals are absent (TNFSF11 gene mutations) or the pathway is interrupted by the lack of cytokine receptors (TNFRSF11A and CSF1R gene mutations), osteoclast precursors are not able to differentiate into mature osteoclast causing osteoclast-poor forms of osteopetrosis. Alternatively, if osteopetrosis is caused by mutations in genes encoding for protein necessary for bone resorption, the disease is defined as osteoclast-rich osteopetrosis. On the right of the figure, are indicated genes involved in bone resorption activity with different roles: i.e., acidification of resorption lacunae and pH regulation (TCIRG1, CLCN7, OSTM1, and CAII), vesicular trafficking and sorting of protein complex to the membrane (SNX10 and PLEKHM1), cytoskeletal rearrangement for ruffle border formation (FERMT3 and LRRK1). Other molecules involved in different signal transductions, essential for osteoclast functions (MITF, LRP5, and IKBKG) are reported.