Intracellular membrane trafficking in bone resorbing osteoclasts

Abstract

There is ample evidence now that the two major events in bone resorption, namely dissolution of hydroxyapatite and degradation of the organic matrix, are performed by osteoclasts. The resorption cycle involves several specific cellular activities, where intracellular vesicular trafficking plays a crucial role. Although details of these processes started to open up only recently, it is clear that vesicular trafficking is needed in several specific steps of osteoclast functioning. Several plasma membrane domains are formed during the polarization of the resorbing cells. Multinucleated osteoclasts create a tight sealing to the extracellular matrix as a first indicator of their resorption activity. Initial steps of the sealing zone formation are alpha(v)beta(3)-integrin mediated, but the final molecular interaction(s) between the plasma membrane and mineralized bone matrix is still unknown. A large number of acidic intracellular vesicles then fuse with the bone-facing plasma membrane to form a ruffled border membrane, which is the actual resorbing organelle. The formation of a ruffled border is regulated by a small GTP-binding protein, rab7, which indicates the late endosomal character of the ruffled border membrane. Details of specific membrane transport processes in the osteoclasts, e.g., the formation of the sealing zone and transcytosis of bone degradation products from the resorption lacuna to the functional secretory domain remain to be clarified. It is tempting to speculate that specific features of vesicular trafficking may offer several potential new targets for drug therapy of bone diseases.

The anion exchanger Ae2 is required for enamel maturation in mouse teeth

“…Assuming that bicarbonate is extruded into the forming enamel by the distal membranes, such concept requires that to maintain electro-neutrality protons are pumped away from the enamel compartment by a proton pump in the basolateral membranes (see for ion transporting epithelial cells: van Adelsberg et al, 1993)). Remarkably however, maturation stage ameloblasts express a proton pump in the apical membrane (Lin et al, 1994), identical to the one found in the boneresorbing osteoclasts (vacuolar H + -ATPase, (Mulari et al, 2003)). The location of this vacuolar H + -ATPase suggests paradoxically that the ameloblasts are secreting protons into the forming enamel instead of bicarbonate.…”

Modulation of osteoclast differentiation and bone resorption by Rho GTPases

“…85 It is mainly controlled by the small GTPases of the Rab family (for a detailed review, see 86 ) and more particularly Rab7 which regulates the late stages of the endosomal pathway from the basolateral membrane to the ruffled border. 87 In resorbing osteoclasts, Rac1 and Rab7 colocalization and interaction at the vesicle fusion zone of the ruffled border suggest a possible role of Rac1 in the formation of this structure.…”

Estudo da osteoclastogênese e da remodelação óssea durante a formação e erupção de molares de ratos tratados com bisfosfonatos.

“…The activated clastic cell present four different specialized membrane domains: the sealing zone and ruffled border that face the bone matrix, the basolateral domain and the functional secretory domain, which are not in contact with the bone matrix but with the extracellular fluid and other cells (Mulari et al, 2003). Fig.…”

“…Regulation and balancing of intracellular pH during acid secretion is maintained by a HCO 3 − /Cl − exchanger located at the basolateral membrane. This structure transports the excess of intracellular HCO 3 − ions outside the cells thus, preventing intracellular alkalinization, while importing chloride ions inside the cell for secretion to the resorption lacuna (Mulari et al, 2003). Once the mineral is dissolved, the organic phase is exposed to proteolytic enzymes synthesized and secreted by the clastic cell into the resorbing lacuna.…”

“…The degradation products are uptaken by the clastic cell in the resorption site, and vesicles containing organic and inorganic material are transported to the functional secretory domain at the plasma membrane. This mechanism allows these cells to maintain resorptive activity throughout their active life-span without accumulation of degradation products in the Howship's lacuna (Mulari et al, 2003).…”