SIKs Control Osteocyte Responses to Parathyroid Hormone

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Oct 21

PMID 27759007

Citations 83

Authors

Marc N Wein

Yanke Liang

Olga Goransson

Thomas B Sundberg

Jinhua Wang

Elizabeth A Williams

Maureen J OMeara

Nicolas Govea

Belinda Beqo

Shigeki Nishimori

Kenichi Nagano

Daniel J Brooks

Janaina S Martins

Braden Corbin

Anthony Anselmo

Ruslan Sadreyev

Joy Y Wu

Kei Sakamoto

Marc Foretz

Ramnik J Xavier

Roland Baron

Mary L Bouxsein

Thomas J Gardella

Paola Divieti-Pajevic

Nathanael S Gray

Henry M Kronenberg

Affiliations

Soon will be listed here.

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.

Citing Articles

Bioactive peptides and proteins for tissue repair: microenvironment modulation, rational delivery, and clinical potential.

Hao Z, Zhang Z, Wang Z, Wang Y, Chen J, Chen T Mil Med Res. 2024; 11(1):75.

PMID: 39639374 PMC: 11619216. DOI: 10.1186/s40779-024-00576-x.

Recent Strategies and Advances in Hydrogel-Based Delivery Platforms for Bone Regeneration.

Wang X, Zeng J, Gan D, Ling K, He M, Li J Nanomicro Lett. 2024; 17(1):73.

PMID: 39601916 PMC: 11602938. DOI: 10.1007/s40820-024-01557-4.

Stimulation of fracture mineralization by salt-inducible kinase inhibitors.

Momenzadeh K, Yeritsyan D, Abbasian M, Kheir N, Hanna P, Wang J Front Bioeng Biotechnol. 2024; 12:1450611.

PMID: 39359266 PMC: 11445660. DOI: 10.3389/fbioe.2024.1450611.

Understanding the roles of salt-inducible kinases in cardiometabolic disease.

Shi F Front Physiol. 2024; 15:1426244.

PMID: 39081779 PMC: 11286596. DOI: 10.3389/fphys.2024.1426244.

PTH receptor signalling, osteocytes and bone disease induced by diabetes mellitus.

Marino S, Bellido T Nat Rev Endocrinol. 2024; 20(11):661-672.

PMID: 39020007 DOI: 10.1038/s41574-024-01014-7.

References

Taniguchi M, Carreira M, Smith L, Zirlin B, Neve R, Cowan C . Histone deacetylase 5 limits cocaine reward through cAMP-induced nuclear import. Neuron. 2012; 73(1):108-20. PMC: 3259532. DOI: 10.1016/j.neuron.2011.10.032. View

Sasagawa S, Takemori H, Uebi T, Ikegami D, Hiramatsu K, Ikegawa S . SIK3 is essential for chondrocyte hypertrophy during skeletal development in mice. Development. 2012; 139(6):1153-63. DOI: 10.1242/dev.072652. View

Parra M, Verdin E . Regulatory signal transduction pathways for class IIa histone deacetylases. Curr Opin Pharmacol. 2010; 10(4):454-60. DOI: 10.1016/j.coph.2010.04.004. View

Kramer I, Loots G, Studer A, Keller H, Kneissel M . Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice. J Bone Miner Res. 2009; 25(2):178-89. PMC: 3153379. DOI: 10.1359/jbmr.090730. View

Popov S, Takemori H, Tokudome T, Mao Y, Otani K, Mochizuki N . Lack of salt-inducible kinase 2 (SIK2) prevents the development of cardiac hypertrophy in response to chronic high-salt intake. PLoS One. 2014; 9(4):e95771. PMC: 3994160. DOI: 10.1371/journal.pone.0095771. View

Fu Q, Jilka R, Manolagas S, OBrien C . Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. J Biol Chem. 2002; 277(50):48868-75. DOI: 10.1074/jbc.M208494200. View

Rhee Y, Allen M, Condon K, Lezcano V, Ronda A, Galli C . PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling. J Bone Miner Res. 2010; 26(5):1035-46. PMC: 3179307. DOI: 10.1002/jbmr.304. View

Baertschi S, Baur N, Lueders-Lefevre V, Voshol J, Keller H . Class I and IIa histone deacetylases have opposite effects on sclerostin gene regulation. J Biol Chem. 2014; 289(36):24995-5009. PMC: 4155667. DOI: 10.1074/jbc.M114.564997. View

Harvey N, Dennison E, Cooper C . Osteoporosis: impact on health and economics. Nat Rev Rheumatol. 2010; 6(2):99-105. DOI: 10.1038/nrrheum.2009.260. View

10.

Fu Q, Manolagas S, OBrien C . Parathyroid hormone controls receptor activator of NF-kappaB ligand gene expression via a distant transcriptional enhancer. Mol Cell Biol. 2006; 26(17):6453-68. PMC: 1592840. DOI: 10.1128/MCB.00356-06. View

11.

Yahara Y, Takemori H, Okada M, Kosai A, Yamashita A, Kobayashi T . Pterosin B prevents chondrocyte hypertrophy and osteoarthritis in mice by inhibiting Sik3. Nat Commun. 2016; 7:10959. PMC: 4820810. DOI: 10.1038/ncomms10959. View

12.

Shimizu E, Selvamurugan N, Westendorf J, Olson E, Partridge N . HDAC4 represses matrix metalloproteinase-13 transcription in osteoblastic cells, and parathyroid hormone controls this repression. J Biol Chem. 2010; 285(13):9616-9626. PMC: 2843211. DOI: 10.1074/jbc.M109.094862. View

13.

Cheloha R, Gellman S, Vilardaga J, Gardella T . PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol. 2015; 11(12):712-24. PMC: 4651712. DOI: 10.1038/nrendo.2015.139. View

14.

Obri A, Makinistoglu M, Zhang H, Karsenty G . HDAC4 integrates PTH and sympathetic signaling in osteoblasts. J Cell Biol. 2014; 205(6):771-80. PMC: 4068141. DOI: 10.1083/jcb.201403138. View

15.

Grozinger C, Schreiber S . Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proc Natl Acad Sci U S A. 2000; 97(14):7835-40. PMC: 16631. DOI: 10.1073/pnas.140199597. View

16.

St John H, Hansen S, Pike J . Analysis of SOST expression using large minigenes reveals the MEF2C binding site in the evolutionarily conserved region (ECR5) enhancer mediates forskolin, but not 1,25-dihydroxyvitamin D or TGFβ responsiveness. J Steroid Biochem Mol Biol. 2015; 164:277-280. PMC: 4781661. DOI: 10.1016/j.jsbmb.2015.09.005. View

17.

Yang D, Guo J, Divieti P, Shioda T, Bringhurst F . CBP/p300-interacting protein CITED1 modulates parathyroid hormone regulation of osteoblastic differentiation. Endocrinology. 2008; 149(4):1728-35. PMC: 2276703. DOI: 10.1210/en.2007-0826. View

18.

Soriano P, Montgomery C, Geske R, Bradley A . Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 1991; 64(4):693-702. DOI: 10.1016/0092-8674(91)90499-o. View

19.

Saini V, Marengi D, Barry K, Fulzele K, Heiden E, Liu X . Parathyroid hormone (PTH)/PTH-related peptide type 1 receptor (PPR) signaling in osteocytes regulates anabolic and catabolic skeletal responses to PTH. J Biol Chem. 2013; 288(28):20122-34. PMC: 3711281. DOI: 10.1074/jbc.M112.441360. View

20.

Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng J . Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011; 17(10):1231-4. DOI: 10.1038/nm.2452. View