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Kcnn4 – a novel regulator osteoclastic resorption and bone turnover
DOI:10.1038/bonekey.2014.111
Kang et al. performed a genome-wide linkage study in rats that were the result of a cross between Wistar Kyoto and Lewis strains, which have key differences in the way they form multinucleate giant cells (MGCs). MGCs and osteoclasts in bone are formed from macrophages that fuse. Determinants of this fusion could be important in inflammatory disease and bone homeostasis.
The linkage study identified 2357 transcripts showing significant linkage to expression quantitative trait loci (eQTLs). Around 67% were cis-regulated with the remainder being trans-regulated. A large trans-eQTL hotspot was identified on chromosome 9 that trans-regulated the expression of 190 transcripts, revealing a gene coexpression network, designated a macrophage multinucleation network.
Further experiments using rat and human samples showed that this network is under trans-acting genetic control of the Trem2 gene. The authors identified Kcnn4 as the eQTL most significantly trans-regulated by Trem2. Kcnn4 knockout mice showed a significant increase in bone density and mass compared to wild-type mice; these mice had abnormally low numbers of TRAP-positive osteoclasts and fewer osteoclasts per unit of bone surface.
The authors conclude that Kcnn4 is an important regulator of bone turnover through its effect on osteoclast formation. They also suggest that targeting Kcnn4 could be used therapeutically in inflammatory conditions in which there is osteoclast or MCG activation.
Editor’s comment: Kcnn4 may become a therapeutic target for inhibiting chronic inflammation and also bone resorption that is enhanced by an inflammatory disease process.
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