Osteoclasts' Ability to Generate Trenches Rather Than Pits Depends on High Levels of Active Cathepsin K and Efficient Clearance of Resorption Products.

Xenia G Borggaard,Kent Søe,Jean-Marie Delaissé,Dinisha C Pirapaharan

doi:10.3390/ijms21165924

Abstract

Until recently, it was well-accepted that osteoclasts resorb bone according to the resorption cycle model. This model is based on the assumption that osteoclasts are immobile during bone erosion, allowing the actin ring to be firmly attached and thereby provide an effective seal encircling the resorptive compartment. However, through time-lapse, it was recently documented that osteoclasts making elongated resorption cavities and trenches move across the bone surface while efficiently resorbing bone. However, it was also shown that osteoclasts making rounded cavities and pits indeed resorb bone while they are immobile. Only little is known about what distinguishes these two different resorption modes. This is of both basic and clinical interest because these resorption modes are differently sensitive to drugs and are affected by the gender as well as age of the donor. In the present manuscript we show that: 1. levels of active cathepsin K determine the switch from pit to trench mode; 2. pit and trench mode depend on clathrin-mediated endocytosis; and 3. a mechanism integrating release of resorption products and membrane/integrin recycling is required for prolongation of trench mode. Our study therefore contributes to an improved understanding of the molecular and cellular determinants for the two osteoclastic bone resorption modes.

Highlights

Osteoclasts (OCs) are multinucleated cells that form through fusion of mono-nucleated precursors of the myeloid lineage [1]
These very different shapes of resorption cavities have been recognized for decades, they were over the years thought to be made through the same type of resorption process—explained through the “resorption cycle” model—where osteoclastic bone resorption would go through alternating stages of bone resorption, migration, and reinitiating resorption at a new site [10,11,12,13,14,32]
The present study identifies two unique mechanisms involved in the trench resorption mode (Figure 8). (i) The ability to launch the trench resorption mode depends on whether the levels of active cathepsin K are sufficient, something which is highly variable amongst OCs generated from different individuals

Summary

Introduction

Osteoclasts (OCs) are multinucleated cells that form through fusion of mono-nucleated precursors of the myeloid lineage [1] These are the only cells of the human body that can efficiently dissolve the mineral component through secretion of protons onto the bone surface. A prerequisite for these two essential processes to occur is that OCs form a so-called actin ring, generating a tight contact to the bone surface mediated by densely packed podosomes [7,8] Within this actin ring, a sealed compartment is formed and a specialized membrane area, called the ruffled border, is generated. A sealed compartment is formed and a specialized membrane area, called the ruffled border, is generated This ruffled border mediates both the secretion of protons and collagenolytic enzymes such as cathepsin K onto the bone surface, facilitating bone resorption. The dissolved mineral component and resorption products are taken up through endocytosis and the resulting vesicles are transported to the functional secretory domain (FSD) where the vesicles fuse with the cell membrane and release the contents [9]

Methods

Results

Discussion

Conclusion