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

Natalie A Diepenhorst1, Katie Leach1, Andrew N Keller1

  • 1Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.

British Journal of Pharmacology
|May 2, 2018
PubMed
Abstract

Insights

The calcimimetic cinacalcet, unlike other tested compounds, inhibits osteoclast function, suggesting potential for osteoporosis treatment. Strontium (Sr2+o) also impacts bone cells via the calcium-sensing receptor.

Area of Science:

  • Pharmacology
  • Bone Biology
  • Molecular Signaling

Background:

  • Strontium ranelate, an osteoporosis drug, acts partly via the calcium-sensing (CaS) receptor.
  • The potential of CaS receptor positive allosteric modulators (calcimimetics) as osteoporosis therapies is unexplored.

Purpose of the Study:

  • To investigate if calcimimetics can serve as alternative or adjunctive therapies to strontium for osteoporosis.
  • To compare the effects of different calcimimetics on CaS receptor signaling and osteoclast function.

Main Methods:

  • Assessed three calcimimetics (cinacalcet, AC-265347, BTU-compound 13) in G protein signaling and trafficking assays in HEK293 cells.
  • Evaluated calcimimetics' effects on human osteoclast differentiation, TRAP activity, and resorption in vitro.
  • Tested calcimimetics alone and with extracellular calcium (Ca2+o) or strontium (Sr2+o).

Main Results:

  • Sr2+o activated CaS receptor signaling similarly to Ca2+o and inhibited osteoclast maturation and resorption.
  • Calcimimetics potentiated Ca2+o- and Sr2+o-mediated CaS receptor signaling with biased profiles.
  • Only cinacalcet normalized CaS receptor trafficking and significantly inhibited osteoclast TRAP activity and resorption.

Conclusions:

  • AC-265347 and BTU-compound 13 did not replicate Sr2+o's inhibitory effects on osteoclasts.
  • Cinacalcet's inhibition of osteoclast function suggests a potential role in treating bone diseases like osteoporosis.
  • Calcimimetics exhibit distinct effects on CaS receptor signaling and osteoclast biology.

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