Regulation of osteoclasts by membrane-derived lipid mediators

Abstract

Osteoclasts are bone-resorbing cells of monocytic origin. An imbalance between bone formation and resorption can lead to osteoporosis or osteopetrosis. Osteoclastogenesis is triggered by RANKL- and IP3-induced Ca(2+) influx followed by activation of NFATc1, a master transcription factor for osteoclastogenic gene regulation. During differentiation, osteoclasts undergo cytoskeletal remodeling to migrate and attach to the bone surface. Simultaneously, they fuse with each other to form multinucleated cells. These processes require PI3-kinase-dependent cytoskeletal protein activation to initiate cytoskeletal remodeling, resulting in the formation of circumferential podosomes and fusion-competent protrusions. In multinucleated osteoclasts, circumferential podosomes mature into stabilized actin rings, which enables the formation of a ruffled border where intensive membrane trafficking is executed. Membrane lipids, especially phosphoinositides, are key signaling molecules that regulate osteoclast morphology and act as second messengers and docking sites for multiple important effectors. We examine the critical roles of phosphoinositides in the signaling cascades that regulate osteoclast functions.

Fig. 1

IP3 instigates the activation and amplification of NFATc1. Depicted above is a schematic illustrating the stages of osteoclast differentiation, including recruitment of progenitors to the bone surface, cell–cell fusion, formation of the actin ring and ruffled border and bone resorption. In the early phase of differentiation (red-boxed), osteoclastogenesis is triggered by RANKL–RANK signaling, which activates PLCγ2 to generate IP3 from PI(4,5)P2 in the plasma membrane. IP3 then stimulates calcium oscillations, which are required for subsequent activation of NFATc1. Knockout of the molecules in red have bone-related phenotypes largely because of impaired osteoclast differentiation (see the text for details). Red dotted lines indicate interactions between PIs and proteins. The dotted arrow indicates the Ca²⁺ oscillation-independent pathway to NFATc1 activation. This figure is modified from Kuroda et al., World Journal of Orthopedics (in press)

Fig. 2

PI(3,4,5)P3 regulates osteoclast adhesion, motility, and ruffled border function. In the later phase of differentiation (red-boxed phase in the top schematic), signaling downstream of c-fms, RANK and α_vβ₃ integrin activates PI3-kinase, triggering the production of PI(3,4,5)P3 in the plasma membrane. PI(3,4,5)P3 then recruits and/or activates cytosolic proteins, which are important for cytoskeletal rearrangement. Knockouts of the molecules in red have bone-related phenotypes because of functional defects in osteoclasts (see the text for details). Blue arrows indicate phosphorylation. Red dotted lines indicate interactions between PIs and proteins. Small GTPases are encircled in green, GEF/GAP in blue, and kinases/phosphatases in yellow

Fig. 3

Vesicular trafficking enables bone resorption. In the resorbing phase (red-boxed phase in the top schematic), Rab GTPases mediate vesicle trafficking, while the fusion of vesicles with the ruffled border to release acids and hydrolases is mediated by Syt VII and Atg5. Dynamin-mediated endocytosis clears degraded materials. Knockouts or mutations of the molecules in red have bone-related phenotypes because of functional defects in osteoclasts (see text for details)