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Robinson LJ , Soboloff J , Tourkova IL , Larrouture QC , Witt MR , Gross S , Hooper R , Samakai E , Worley PF , Barnett JB , Blair HC
The function of the calcium channel Orai1 in osteoclast development
Faseb j. 2021 Jun;35(6) :e21653
PMID: 34009685   
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Abstract
To determine the intrinsic role of Orai1 in osteoclast development, Orai1-floxed mice were bred with LysMcre mice to delete Orai1 from the myeloid lineage. PCR, in situ labelling and Western analysis showed Orai1 deletion in myeloid-lineage cells, including osteoclasts, as expected. Surprisingly, bone resorption was maintained in vivo, despite loss of multinucleated osteoclasts; instead, a large number of mononuclear cells bearing tartrate resistant acid phosphatase were observed on cell surfaces. An in vitro resorption assay confirmed that RANKL-treated Orai1 null cells, also TRAP-positive but mononuclear, degraded matrix, albeit at a reduced rate compared to wild type osteoclasts. This shows that mononuclear osteoclasts can degrade bone, albeit less efficiently. Further unexpected findings included that Orai1(fl/fl) -LysMcre vertebrae showed slightly reduced bone density in 16-week-old mice, despite Orai1 deletion only in myeloid cells; however, this mild difference resolved with age. In summary, in vitro analysis showed a severe defect in osteoclast multinucleation in Orai1 negative mononuclear cells, consistent with prior studies using less targeted strategies, but with evidence of resorption in vivo and unexpected secondary effects on bone formation leaving bone mass largely unaffected.
Notes
1530-6860 Robinson, Lisa J Soboloff, Jonathan Tourkova, Irina L Larrouture, Quitterie C Witt, Michelle R Orcid: 0000-0001-9483-8346 Gross, Scott Hooper, Robert Samakai, Elsie Worley, Paul F Barnett, John B Orcid: 0000-0001-6547-2381 Blair, Harry C BX002490/U.S. Department of Veterans Affairs (VA)/ AR065407/HHS | National Institutes of Health (NIH)/ AR076146/HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)/ GM104942/HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ Journal Article United States FASEB J. 2021 Jun;35(6):e21653. doi: 10.1096/fj.202001921RR.