Abstract
Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH.
Highlights
Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption
A major arm of PTH signalling in osteocytes involves Salt inducible kinases (SIKs) inhibition, as revealed by RNA-seq analysis of PTH- versus YKL-05-093-treated osteocytes
Having previously demonstrated that HDAC5 blocks MEF2C-driven SOST expression in osteocytes[16], we sought to determine whether HDAC5 and SOST interact in vivo to control bone mass
Summary
Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. Among the mechanisms through which PTH stimulates new bone formation, down-regulation of SOST expression in osteocytes plays an important role[8,9,10]. Like class IIa HDACs, cAMP-regulated transcriptional coactivators (CRTC) proteins shuttle from the cytoplasm to the nucleus where they function as CREB coactivators[19]. Both HDAC4/5 and CRTC2 are known substrates of salt inducible kinases (SIKs)[19,20,21,22], and SIK3 deficiency in growth plate chondrocytes increases nuclear HDAC4 and delays MEF2-driven chondrocyte hypertrophy[21]
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