Abstract
The current models of osteoclastic bone resorption focus on immobile osteoclasts sitting on the bone surface and drilling a pit into the bone matrix. It recently appeared that many osteoclasts also enlarge their pit by moving across the bone surface while resorbing. Drilling a pit thus represents only the start of a resorption event of much larger amplitude. This prolonged resorption activity significantly contributes to pathological bone destruction, but the mechanism whereby the osteoclast engages in this process does not have an answer within the standard bone resorption models. Herein, we review observations that lead to envision how prolonged resorption is possible through simultaneous resorption and migration. According to the standard pit model, the “sealing zone” which surrounds the ruffled border (i.e., the actual resorption apparatus), “anchors” the ruffled border against the bone surface to be resorbed. Herein, we highlight that continuation of resorption demands that the sealing zone “glides” inside the cavity. Thereby, the sealing zone emerges as the structure responsible for orienting and displacing the ruffled border, e.g., directing resorption against the cavity wall. Importantly, sealing zone displacement stringently requires thorough collagen removal from the cavity wall - which renders strong cathepsin K collagenolysis indispensable for engagement of osteoclasts in cavity-enlargement. Furthermore, the sealing zone is associated with generation of new ruffled border at the leading edge, thereby allowing the ruffled border to move ahead. The sealing zone and ruffled border displacements are coordinated with the migration of the cell body, shown to be under control of lamellipodia at the leading edge and of the release of resorption products at the rear. We propose that bone resorption demands more attention to osteoclastic models integrating resorption and migration activities into just one cell phenotype.
Highlights
Specialty section: This article was submitted to Cellular Biochemistry, a section of the journal Frontiers in Cell and Developmental
The main components of the resorption machinery have been identified (Väänänen et al, 2000; Coxon and Taylor, 2008; Feng and Teitelbaum, 2013; Ng et al, 2019) and are usually pictured as Mechanism of Prolonged Bone Resorption in Figure 1A. (i) The ruffled border is a zone of the plasma membrane facing the bone surface and is specialized in secretion of resorption agents and uptake of resorption products - much like the boring head of a tunneling machine integrating destruction and evacuation of debris. (ii) The sealing zone (SZ) surrounds the ruffled border and delineates the area of bone surface to be resorbed
The SZ is commonly believed to prevent the diffusion of resorption agents to the surrounding bone surface and to anchor the bone resorption compartment to the bone surface. (iii) An intricate network of vesicles trafficking through the cell deliver resorption agents to the resorption compartment and transport resorption products from the ruffled border to the basolateral domain. (iv) A complex cytoskeletal organization is involved in this intracellular trafficking and connected to the SZ
Summary
Bone resorption is necessary to allow bone modeling and remodeling, and may become deleterious in pathological situations. The ruffled border invades the bone matrix perpendicularly to the bone surface and generates a pit (Figure 1A) According to this model, the resorption event remains stationary on the bone surface for its whole duration (typically 2-24 h in bone resorption assays) (Søe and Delaissé, 2017). We review both published and unpublished observations that may help understanding the mechanistic peculiarities of the trench mode vs the pit mode and thereby help comprehending the resorption power beyond what is classically investigated They let us proposing a previously underestimated regulatory role of the collagenolysis rate vs demineralization rate, as it determines whether the SZ can move into the excavation - thereby re-orienting the ruffled border and the resorption axis for cavity enlargement. The present analysis invites to improve our view of the bone resorbing osteoclast by taking into account combined resorption and migration
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