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Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodeling
Shigeki Nishimori, … , Henry M. Kronenberg, Marc N. Wein
Shigeki Nishimori, … , Henry M. Kronenberg, Marc N. Wein
Published August 20, 2019
Citation Information: J Clin Invest. 2019;129(12):5187-5203. https://doi.org/10.1172/JCI130126.
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Research Article Bone biology Endocrinology

Salt-inducible kinases dictate parathyroid hormone 1 receptor action in bone development and remodeling

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Abstract

The parathyroid hormone 1 receptor (PTH1R) mediates the biologic actions of parathyroid hormone (PTH) and parathyroid hormone–related protein (PTHrP). Here, we showed that salt-inducible kinases (SIKs) are key kinases that control the skeletal actions downstream of PTH1R and that this GPCR, when activated, inhibited cellular SIK activity. Sik gene deletion led to phenotypic changes that were remarkably similar to models of increased PTH1R signaling. In growth plate chondrocytes, PTHrP inhibited SIK3, and ablation of this kinase in proliferating chondrocytes rescued perinatal lethality of PTHrP-null mice. Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes led to a dramatic increase in bone mass that closely resembled the skeletal and molecular phenotypes observed when these bone cells express a constitutively active PTH1R that causes Jansen’s metaphyseal chondrodysplasia. Finally, genetic evidence demonstrated that class IIa histone deacetylases were key PTH1R-regulated SIK substrates in both chondrocytes and osteocytes. Taken together, our findings establish that SIK inhibition is central to PTH1R action in bone development and remodeling. Furthermore, this work highlights the key role of cAMP-regulated SIKs downstream of GPCR action.

Authors

Shigeki Nishimori, Maureen J. O’Meara, Christian D. Castro, Hiroshi Noda, Murat Cetinbas, Janaina da Silva Martins, Ugur Ayturk, Daniel J. Brooks, Michael Bruce, Mizuki Nagata, Wanida Ono, Christopher J. Janton, Mary L. Bouxsein, Marc Foretz, Rebecca Berdeaux, Ruslan I. Sadreyev, Thomas J. Gardella, Harald Jüppner, Henry M. Kronenberg, Marc N. Wein

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Figure 5

Global molecular concordance between Sik2fl/fl Sik3fl/fl Dmp1-Cre and C1HR mice.

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Global molecular concordance between Sik2fl/fl Sik3fl/fl Dmp1-Cre and C1...
(A) Left: H&E-stained images (original magnification, ×100) in the primary and secondary spongiosa of 6-week-old Col1a1-PTH1RH223R (C1HR) mice showing increased bone mass and increased marrow stromal cells. Middle: TRAP-stained images (original magnification, ×20) revealing increased osteoclasts on trabecular surfaces of C1HR mice. Right: Immunostaining for activated β-catenin reveals increased WNT pathway activity in C1HR animals. See Figure 3, B and C, and Figure 4E for similarities to Sik2fl/fl Sik3fl/fl Dmp1-Cre mice. Scale bars: 100 μm for left and right panels, 1 mm for middle panels. (B) RNA-Seq was performed on bone RNA isolated from Sik2fl/fl Sik3fl/fl Dmp1-Cre mice (n = 6) with n = 8 littermate controls, and C1HR mice (n = 12) with n = 11 littermate controls. Volcano plots show the relationship between fold change and statistical significance across these 2 data sets. (C) Venn diagram analysis of lists of differentially expressed genes (DEGs) (log2 FC > 2, FDR < 0.05) between the 2 comparisons. Hypergeometric P values for all overlap analyses are less than 0.05. (D) Heatmap showing extensive coregulation of gene expression in SIK2/3 mutant and C1HR mice. Each row represents a distinct DEG (encompassing all genes found in the first Venn diagram in C), and each column represents a mouse of the indicated genotype. The log2 fold change of each gene is expressed versus the mean of the control mice. (E) Scatterplot demonstrating extensive coregulation between SIK2/3 mutants and C1HR mice. Each dot represents the average log2 fold change for all genes detected by RNA-Seq comparing mutant versus control. Linear regression analysis between the 2 data sets reveals P < 0.0001, slope = 0.9112, R2 = 0.5914. (F) Similar scatterplot demonstrating relative lack of concordance between effects of SIK2/3 deletion in osteoblasts/osteocytes and effects of 2 weeks of sclerostin antibody treatment. Linear regression analysis between the 2 data sets reveals P < 0.0001, slope = 0.1155, R2 = 0.051. See also Supplemental Figures 6–8.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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