Abstract
Osteoclasts are multinucleated bone degrading cells. Phosphate is an important constituent of mineralized bone and released in significant quantities during bone resorption. Molecular contributors to phosphate transport during the resorptive activity of osteoclasts have been controversially discussed. This study aimed at deciphering the role of sodium-dependent phosphate transporters during osteoclast differentiation and bone resorption. Our studies reveal RANKL-induced differential expression of sodium-dependent phosphate transport protein IIa (NaPi-IIa) transcript and protein during osteoclast development, but no expression of the closely related NaPi-IIb and NaPi-IIc SLC34 family isoforms. In vitro studies employing NaPi-IIa-deficient osteoclast precursors and mature osteoclasts reveal that NaPi-IIa is dispensable for bone resorption and osteoclast differentiation. These results are supported by the analysis of structural bone parameters by high-resolution microcomputed tomography that yielded no differences between adult NaPi-IIa WT and KO mice. By contrast, both type III sodium-dependent phosphate transporters Pit-1 and Pit-2 were abundantly expressed throughout osteoclast differentiation, indicating that they are the relevant sodium-dependent phosphate transporters in osteoclasts and osteoclast precursors. We conclude that phosphate transporters of the SLC34 family have no role in osteoclast differentiation and function and propose that Pit-dependent phosphate transport could be pivotal for bone resorption and should be addressed in further studies.
Highlights
Phosphate is a major constituent of hydroxyapatite (Ca3(PO4)2Ca(OH)2) and of mineralized bone
Of the three types of sodium-dependent phosphate transporter classes recognized in mammals (types I (SLC17 family), II (SLC34 family) and III (SLC20 family)), type II and type III phosphate transporters were previously identified in osteoclasts [8,12]
While several sodium-dependent phosphate transporters were found to be expressed in osteoclast precursors and mature osteoclasts, the time course of expression during RANKL-mediated osteoclast differentiation has not been explored [8,10,12]
Summary
Phosphate is a major constituent of hydroxyapatite (Ca3(PO4)2Ca(OH)2) and of mineralized bone. Osteoclasts are polarized cells with a basolateral side facing the blood compartment and an apical side characterized by a ruffled border facing bone matrix and delineating a resorption lacuna. The high H+ concentration is critical for the optimal catalytic activity of bone matrix degrading enzymes and supports the dissolution of hydroxyapatite [2]. The latter process leads to the liberation of large amounts of calcium and phosphate in the hemivacuole, where concentrations of up to 40 mM calcium can be reached [3]. During active bone resorption, osteoclasts are exposed to high ambient concentrations of calcium and phosphate, especially at the apical, resorbing site. Ito et al were unable to detect NaPi-IIa protein expression in osteoclasts by Western blot or immunofluorescence [12]
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