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

• Published in: British journal of pharmacology 2018-11, Vol.175 (21), p.4095-4108
• Main Authors: Diepenhorst, Natalie A, Leach, Katie, Keller, Andrew N, Rueda, Patricia, Cook, Anna E, Pierce, Tracie L, Nowell, Cameron, Pastoureau, Philippe, Sabatini, Massimo, Summers, Roger J, Charman, William N, Sexton, Patrick M, Christopoulos, Arthur, Langmead, Christopher J
• Format: Article
• Language: English
• Subjects: Acid phosphatase; Acid phosphatase (tartrate-resistant); Acid resistance; Allosteric properties; Allosteric Regulation - drug effects; Benzothiazole; Bone mineral density; Bone resorption; Calcimimetic Agents - chemistry; Calcimimetic Agents - pharmacology; Calcium; Calcium (extracellular); Calcium compounds; Calcium sulfides; Cell differentiation; Cell Differentiation - drug effects; Cell surface; Cells, Cultured; Cinacalcet - chemistry; Cinacalcet - pharmacology; Endoplasmic reticulum; HEK293 Cells; Humans; Hydroxyapatite; Molecular Structure; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteoporosis; Pharmacology; Receptor mechanisms; Receptors, Calcium-Sensing - antagonists & inhibitors; Receptors, Calcium-Sensing - metabolism; Research Paper; Strontium; Strontium - chemistry; Strontium - pharmacology; Themed Section: Research Paper; Urea
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14344

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