Rho GTPases in osteoclasts: Orchestrators of podosome arrangement

Abstract

Cells from the myeloid lineage, namely macrophages, dendritic cells and osteoclasts develop podosomes instead of stress fibers and focal adhesions to adhere and migrate.Podosomes share many components with focal adhesions but differ in their molecular organization, with a dense core of polymerized actin surrounded by scaffolding proteins, kinases and integrins. Podosomes are found either isolated both in macrophages and dendritic cells or arranged into superstructures in osteoclasts. When osteoclasts resorb bone, they form an F-actin rich sealing zone, which is a dense array of connected podosomes that firmly anchors osteoclasts to bone. It delineates a compartment in which protons and proteases are secreted to dissolve and degrade the mineralized matrix. Since Rho GTPases have been shown to control F-actin stress fibers and focal adhesions in mesenchymal cells, the question of whether they could also control podosome formation and arrangement in cells from the myeloid lineage, and particularly in osteoclasts, rapidly emerged. This article considers recent advances made in our understanding of podosome arrangements in osteoclasts and how Rho GTPases may control it.

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

“…However, miR‐31a‐5p reduction in the supernatant not only led to decreased osteoclastogenesis and bone resorption but also elevated expression of RhoA. Although studies have demonstrated that RhoA activity, controlling cytoskeleton organization, is crucial for osteoclast maturation and bone resorption (Chellaiah et al., 2000), it has also been reported that inhibition of RhoA maintained the podosomal and sealing zone stability, which is possibly correlated with increased microtubule acetylation and stabilization in osteoclasts (Destaing et al., 2005; Granot‐Attas, Luxenburg, Finkelshtein, & Elson, 2009; Ory, Brazier, Pawlak, & Blangy, 2008; Wu et al., 2017). In our study, increased RhoA expression through miR‐31a‐5p inhibition reduced osteoclastogenesis, while decreased RhoA expression favored osteoclastogenesis.…”

The Rac1 exchange factor Dock5 is essential for bone resorption by osteoclasts

“…(8) As major cellular regulators of actin organization, Rho GTPase signaling pathways are also essential players in sealing zone assembly. (9) Rho GTPases cycle between inactive GDP-bound and active GTP-bound states. In their active form, they bind to effector proteins and engage numerous signaling pathways.…”

Invadosomes at a glance

“…Besides their other crucial functions in invadosome regulation (see above and below), Rho GTPases also have a role in the subcellular positioning of invadosomes -for example, CDC42 is involved in the recruitment of podosomes to the leading edge of migrating dendritic cells (Burns et al, 2001), and microtubule-dependent positioning of peripheral arrays of podosomes (so-called podosome belts) in osteoclasts is regulated by a pathway that is controlled by RhoA and histone deacetylase 6 (Destaing et al, 2005;Ory et al, 2008). Finally, microtubules and microtubulebased motor proteins such as the kinesin KIF1C also play a role in the fission (the formation of new podosomes by splitting off from larger precursors) and dissolution processes of podosomes in human macrophages (Kopp et al, 2006).…”