Abstract
Macrophages from mouse strains with the naturally occurring mutation P451L in the purinergic receptor P2X7 have impaired responses to agonists (1). Because P2X7 receptors are expressed in bone cells and are implicated in bone physiology, we asked whether strains with the P451L mutation have a different bone phenotype. By sequencing the most common strains of inbred mice, we found that only a few strains (BALB, NOD, NZW, and 129) were harboring the wild allelic version of the mutation (P451) in the gene for the purinergic receptor P2X7. The strains were compared by means of dual energy X-ray absorptiometry (DXA), bone markers, and three-point bending. Cultured osteoclasts were used in the ATP-induced pore formation assay. We found that strains with the P451 allele (BALB/cJ and 129X1/SvJ) had stronger femurs and higher levels of the bone resorption marker C-telopeptide collagen (CTX) compared to C57Bl/6 (B6) and DBA/2J mice. In strains with the 451L allele, pore-formation activity in osteoclasts in vitro was lower after application of ATP. In conclusion, two strains with the 451L allele of the naturally occurring mutation P451L, have weaker bones and lower levels of CTX, suggesting lower resorption levels in these animals, which could be related to the decreased ATP-induced pore formation observed in vitro. The importance of these findings for the interpretation of the earlier reported effects of P2X7 in mice is discussed, along with strategies in developing a murine model for testing the therapeutic effects of P2X7 agonists and antagonists upon postmenopausal osteoporosis.
Highlights
In the past decade several reports have shown that P2receptor signalling plays a central role in bone physiology [1,2,3,4,5]
Because P2X7 receptors are expressed in bone cells and are implicated in bone physiology, we asked whether strains with the P451L mutation have a different bone phenotype
We found that strains with the P451 allele (BALB/cJ and 129X1/SvJ) had stronger femurs and higher levels of the bone resorption marker C-telopeptide collagen (CTX) compared to C57Bl/6 (B6) and DBA/2J mice
Summary
In the past decade several reports have shown that P2receptor signalling plays a central role in bone physiology [1,2,3,4,5]. Bone cells express several types of P2 receptors [6], allowing them to respond differently to nucleotides, depending on the types of nucleotides present, their concentration, and the duration of exposure [7, 8]. Prolonged exposure to high agonist concentrations initiates the formation of large pores in the membrane mediated by the P2 subtype P2X7, a feature often assessed by ATP-induced dye uptake [7, 9]. There are several studies directing a role to the P2X7 receptor in mediating ATP-induced apoptosis in other cell types [7] and increased osteoclast numbers have been found in mice with ablation of the P2X7 receptor (P2X7−/− mice) [3]. The P2X7 receptors are expressed in both osteoclast precursors and resorbing osteoclasts [8, 14, 15], and in addition
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