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Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity.

Abstract：

BACKGROUND AND PURPOSE:Strontium ranelate, a drug approved and until recently used for the treatment of osteoporosis, mediates its effects on bone at least in part via the calcium-sensing (CaS) receptor. However, it is not known whether bone-targeted CaS receptor positive allosteric modulators (PAMs; calcimimetics) represent an alternative (or adjunctive) therapy to strontium (Sr2+o ). EXPERIMENTAL APPROACH:We assessed three structurally distinct calcimimetics [cinacalcet, AC-265347 and a benzothiazole tri-substituted urea (BTU-compound 13)], alone and in combination with extracellular calcium (Ca2+o ) or Sr2+o , in G protein-dependent signalling assays and trafficking experiments in HEK293 cells and their effects on cell differentiation, tartrate-resistant acid phosphatase (TRAP) activity and hydroxyapatite resorption assays in human blood-derived osteoclasts. KEY RESULTS:Sr2+o activated CaS receptor-dependent signalling in HEK293 cells in a similar manner to Ca2+o , and inhibited the maturation, TRAP expression and hydroxyapatite resorption capacity of human osteoclasts. Calcimimetics potentiated Ca2+o - and Sr2+o -mediated CaS receptor signalling in HEK293 cells with distinct biased profiles, and only cinacalcet chaperoned an endoplasmic reticulum-retained CaS mutant receptor to the cell surface in HEK293 cells, indicative of a conformational state different from that engendered by AC-265347 and BTU-compound 13. Intriguingly, only cinacalcet modulated human osteoclast function, reducing TRAP activity and profoundly inhibiting resorption. CONCLUSION AND IMPLICATIONS:Although AC-265347 and BTU-compound 13 potentiated Ca2+o - and Sr2+o -induced CaS receptor activation, they neither replicated nor potentiated the ability of Sr2+o to inhibit human osteoclast function. In contrast, the FDA-approved calcimimetic, cinacalcet, inhibited osteoclast TRAP activity and hydroxyapatite resorption, which may contribute to its clinical effects on bone mineral density LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Diepenhorst NA,Leach K,Keller AN,Rueda P,Cook AE,Pierce TL,Nowell C,Pastoureau P,Sabatini M,Summers RJ,Charman WN,Sexton PM,Christopoulos A,Langmead CJ

doi

10.1111/bph.14344

subject

Has Abstract

pub_date

2018-11-01 00:00:00

pages

4095-4108

issue

eissn

0007-1188

issn

1476-5381

journal_volume

175

pub_type

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Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity.