Membrane Transport Proteins in Osteoclasts: The Ins and Outs

Abstract

During bone resorption, the osteoclast must sustain an extraordinarily low pH environment, withstand immense ionic pressures, and coordinate nutrient and waste exchange across its membrane to sustain its unique structural and functional polarity. To achieve this, osteoclasts are equipped with an elaborate set of membrane transport proteins (pumps, transporters and channels) that serve as molecular 'gatekeepers' to regulate the bilateral exchange of ions, amino acids, metabolites and macromolecules across the ruffled border and basolateral domains. Whereas the importance of the vacuolar-ATPase proton pump and chloride voltage-gated channel 7 in osteoclasts has long been established, comparatively little is known about the contributions of other membrane transport proteins, including those categorized as secondary active transporters. In this Special Issue review, we provide a contemporary update on the 'ins and outs' of membrane transport proteins implicated in osteoclast differentiation, function and bone homeostasis and discuss their therapeutic potential for the treatment of metabolic bone diseases.

Keywords: CLCN7; V-ATPase; bone disease; ion channel; membrane transporter; osteoclast; osteoporosis; solute carrier.

FIGURE 1

Anatomy of the Osteoclast. Illustration of the unique configuration and membrane organization of an osteoclast during active bone resorption. The osteoclast’s specialized plasma membrane domains are labeled and color-coded: Purple = the functional secretory domain, Orange = the basolateral membrane, Yellow = the sealing zone and Green = the ruffled border membrane. Created with BioRender.com.

FIGURE 2

Ins and outs of membrane transport proteins in osteoclasts. (A) Schema depicting the major types of transport proteins and their modes of substrate movement across biological membranes. (B) Model summarizing the reported membrane localization of all the major membrane transport proteins expressed in osteoclasts. Known substrates are indicated in gray. Intracellular compartments correspond to: ER, endoplasmic reticulum; SL, Secretory lysosome; LE, Late endosome; TV, Transcytotic vesicle. Created with BioRender.com.

FIGURE 3

Structure of the V-ATPase proton pump. The V-ATPase complex is composed of two domains: the peri-membranous V₁ domain composed of subunits A to H responsible for the hydrolysis of ATP shown in blue, and the intramembranous V₀ domain who allows the translocation of protons across the membrane shown in purple in the diagram. The V0 domain is composed of the subunits a, e, d and of a hexameric ring formed by subunits c, c′ and c″.