Specialized Roles for Actin in Osteoclasts: Unanswered Questions and Therapeutic Opportunities.

Guanghong Han,Jian Zuo,Lexie Holliday

doi:10.3390/biom9010017

Abstract

Osteoclasts are cells of the hematopoietic lineage that are specialized to resorb bone. In osteoclasts, the actin cytoskeleton engages in at least two unusual activities that are required for resorption. First, microfilaments form a dynamic and structurally elaborate actin ring. Second, microfilaments bind vacuolar H+-ATPase (V-ATPase) and are involved in forming the V-ATPase-rich ruffled plasma membrane. The current review examines these two specialized functions with emphasis on the identification of new therapeutic opportunities. The actin ring is composed of substructures called podosomes that are interwoven to form a cohesive superstructure. Studies examining the regulation of the formation of actin rings and its constituent proteins are reviewed. Areas where there are gaps in the knowledge are highlighted. Microfilaments directly interact with the V-ATPase through an actin binding site in the B2-subunit of V-ATPase. This binding interaction is required for ruffled membrane formation. Recent studies show that an inhibitor of the interaction blocks bone resorption in pre-clinical animal models, including a model of post-menopausal osteoporosis. Because the unusual actin-based resorption complex is unique to osteoclasts and essential for bone resorption, it is likely that deeper understanding of its underlying mechanisms will lead to new approaches to treat bone disease.

Highlights

Because podosomes in the actin rings of resorbing cells are much larger the fact that they recover after photobleaching in the same time suggests much higher rates of actin turnover occur in actin rings of resorbing osteoclasts [32]
The actin ring structure is based on podosomes, structures found in some other cell types
The actin ring structure that the podosomes are organized into is unique to osteoclasts and presumably involves compositional and/or regulatory elements that are distinct from podosomes in other cells

Summary

Introduction

The osteoclast is a cell type that is specialized for invasion through mineralized matrix [1,2]. A surprising early view of the crucial nature and regulation the actin ring in bone resorption infancy, provided a solid structural basis for the research that has of followed. The severe detected surprising early view of the crucial nature and regulation of the actin ringpathologies in bone resorption were when secondary to defects in bone resorption These included failure of The tooth eruption, growth came the tyrosine kinase pp60c‐src was knocked out in mice severe pathologies reduction, and cranial malformation. The brain and platelets, where c-src is most highly expressed, and detected were secondary to defects in bone resorption These included failure of tooth eruption, other tissue and organ systems did not reveal abnormalities. Kindlin-3, a blood cell specific activator of β1, β2, and β3 integrins, which are all found in osteoclasts, results in osteopetrosis in mice associated with dysfunctional actin ring formation [25]. Osteoclasts, along with intercalated cells and proximal tubule cells in the kidney, and cells from a few other locations, express very large amounts of V-ATPase and it is localized in a specialized domain of the plasma membrane when the cells are activated [28]

Actin Dynamics in the Actin Ring

Mechanisms Regulating Microfilament Dynamics in the Actin Ring

Unanswered

Actin and the Formation of the Ruffle Membrane

Summary and Perspectives