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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 7

Class IIa HDACs are key downstream mediators of PTH1R/SIK action in osteoblasts/osteocytes.

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Class IIa HDACs are key downstream mediators of PTH1R/SIK action in oste...
(A) Femurs from 6-week-old mice of the indicated genotypes were analyzed by micro-CT. Full-length images are representative of at least n = 3 mice per genotype; littermate controls were used for all experiments. Mean R1 (midshaft cortical) bone volume fraction (BV/TV, determined from region “1” above including cortical bone) and R2 (trabecular) bone volume fraction (BV/TV, determined from region “2” above excluding cortical bone) (± SD) are shown for each genotype, with sample size analyzed in parentheses. *P < 0.05 vs. WT, #P < 0.05 vs. Sik2/3-DKO. For R1 midshaft whole bone BV/TV comparisons: WT vs. Sik2/3-DKO, P = 0.00053; Sik2/3-DKO vs. Sik2/3 Hdac4/5 quadruple-KO, P = 0.0083. For R2 trabecular BV/TV comparisons: WT vs. Hdac4/5-DKO, P = 0.037; WT vs. Sik2/3-DKO, P = 0.000114; Sik2/3-DKO vs. Sik2/3 Hdac4/5 quadruple-KO, P = 0.000336. One-way ANOVA followed by Dunnett’s multiple-comparisons test was used to determine P values. (B) Representative H&E stain (sample size analyzed of each group is shown in A) of the primary and secondary spongiosa in the proximal tibia at ×100 original magnification. (C) Sclerostin immunohistochemistry from sections in B shown at the level of midshaft cortical bone. Sclerostin immunoreactivity levels are high in HDAC4/5-deficient mice, low in Sik2fl/fl Sik3fl/fl Dmp1-Cre mice, and high in compound HDAC4/5 SIK2/3 mutants. Scale bars: 100 μm for histology panels and 1 mm for micro-CT panels.

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

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