Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption

Tang, C. C. H.; Andrade, Christian D. Castro; O'Meara, Maureen J; Yoon, Sung-Hee; Sato, Tadatoshi; Brooks, Daniel J.; Bouxsein, Mary L.; Martins, Janaina da Silva; Wang, Jinhua; Gray, Nathanael S.; Misof, Barbara M.; Roschger, Paul; Blouin, Stéphane; Klaushofer, Klaus; Velduis-Vlug, Annegreet; Vegting, Yosta; Rosen, Clifford J.; O’Connell, Daniel J.; Sundberg, Thomas B.; Xavier, Ramnik J.; Ung, Peter M.U.; Schlessinger, Avner; Kronenberg, Henry M.; Berdeaux, Rebecca; Foretz, Marc; Wein, Marc N.

doi:10.7554/elife.67772

Cited by 12 publications

(12 citation statements)

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“…It supports a role for SIK inhibition in adipose tissue and represents a potential intervention strategy that could be translated to obesity and cardiometabolic disease in future studies. Of note, a recent study showed that YKL can inhibit both SIKs and colony stimulating factor 1 receptor (CSF1R) to promote bone formation [63]. Although CSF1R inhibition has been reported to result in reduced macrophage accumulation in adipose tissue [64], its role in the adipocyte thermogenic program is yet to be explored, and it is unclear whether CSF1R inhibition also plays a role for the adipose browning phenotypes in the YKL treated mice in our current study.…”

Section: Discussionmentioning

confidence: 76%

Salt-inducible kinase inhibition promotes the adipocyte thermogenic program and adipose tissue browning

Shi

Silva

Liu

et al. 2022

Preprint

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Norepinephrine stimulates the adipose tissue thermogenic program through a beta-adrenergic receptor (Beta AR) - cyclic adenosine monophosphate (cAMP) - protein kinase A (PKA) signaling cascade. Previous work from our lab showed that noncanonical activation of the mechanistic target of rapamycin complex 1 (mTORC1) by PKA is required for the beta AR-stimulation of adipose tissue browning. However, the downstream events triggered by mTORC1 activation that drive this thermogenic response are not well understood. In this study, we used a proteomic approach of Stable Isotope Labeling by/with Amino acids in Cell culture (SILAC) to characterize the global protein phosphorylation profile in brown adipocytes with beta-agonist isoproterenol stimulation and identified salt-inducible kinase 3 (SIK3) as a candidate mTORC1 substrate. SIK3 interacts with RAPTOR, the defining component of the mTORC1 complex, and is phosphorylated at Ser 884 in a mTORC1-dependent manner. Pharmacological SIK inhibition by a pan-SIK inhibitor (HG-9-91-01) in brown adipocytes increases basal Ucp1 gene expression and restores its expression upon either mTORC1 or PKA blockades. Short-hairpin RNA knockdown of Sik3 augments, while overexpression of SIK3 suppresses, Ucp1 gene expression in brown adipocytes. In addition, CRISPR gene-edited Sik3-/- brown adipocytes show enhanced Ucp1 gene expression at basal conditions and after Iso stimulation. Finally, a SIK inhibitor well-tolerated in vivo (YKL-05-099) can stimulate adipose tissue browning and thermogenic gene expression in mouse subcutaneous inguinal adipose tissue, supporting an essential role of SIK inhibition in regulating the adipose tissue browning program in vivo. Taken together, our data reveal that salt-inducible kinases function as a phosphorylation switch for beta-adrenergic activation to drive the adipose thermogenic program and suggest that maneuvers targeting SIKs could be beneficial for obesity and related metabolic disease.

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Section: Discussionmentioning

confidence: 76%

Salt-inducible kinase inhibition promotes the adipocyte thermogenic program and adipose tissue browning

Shi

Silva

Liu

et al. 2022

Preprint

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“…First, we sought to determine whether SIKs participate in any of the acute renal actions of PTH. PTH signaling inhibits SIK cellular activity, so direct small-molecule SIK inhibitors serve as valuable tools to study SIK-dependent and -independent aspects of PTH function ( 24 , 26 – 28 ). Therefore, 13-week-old C57BL6 mice were treated with vehicle; the “first-generation” pan-SIK inhibitor, YKL-05-099; or PTH, and effects on mineral metabolism were assessed.…”

Section: Resultsmentioning

confidence: 99%

“…Because YKL-05-099 is a relatively promiscuous kinase inhibitor ( 26 ), we performed similar studies using SK-124, a selective SIK2/SIK3 inhibitor with improved specificity and bone anabolic action ( 29 ). SK-124 also increased Cyp27b1 and decreased Cyp24a1 expression and increased circulating 1,25-vitamin D levels ( Figure 1, F and G ; Supplemental Figure 1G ; and Supplemental Table 5 ).…”

Section: Resultsmentioning

confidence: 99%

“…Osteoblast/osteocyte-specific SIK2/SIK3 ablation leads to a dramatic increase in bone mass that closely resembles phenotypes observed when a constitutively active PTH receptor is expressed selectively in bone ( 25 ). Ubiquitous/inducible SIK2/SIK3 ablation leads to a comparable, yet somewhat less dramatic, high trabecular bone mass phenotype ( 26 ). Ubiquitous/inducible SIK1/SIK2/SIK3 deletion caused modest increases in trabecular bone mass, with dramatic 1,25-vitamin D–mediated hypercalcemia ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

“…This permits the dephosphorylation of SIK substrates, including class IIa histone deacetylases (HDACs) and CREB-regulated transcriptional coactivator (CRTC) proteins, allowing their translocation into the nucleus to modulate gene expression. SIK gene deletion or pharmacologic inhibition leads to gene expression changes in bone cells, resulting in increased bone formation and dramatic accrual in trabecular bone (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

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A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis

Yoon¹,

Meyer²,

Rivas³

et al. 2023

Journal of Clinical Investigation

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The renal actions of parathyroid hormone (PTH) promote 1,25-vitamin D generation; however, the signaling mechanisms that control PTH-dependent vitamin D activation remain unknown. Here, we demonstrated that salt-inducible kinases (SIKs) orchestrated renal 1,25-vitamin D production downstream of PTH signaling. PTH inhibited SIK cellular activity by cAMP-dependent PKA phosphorylation. Whole-tissue and single-cell transcriptomics demonstrated that both PTH and pharmacologic SIK inhibitors regulated a vitamin D gene module in the proximal tubule. SIK inhibitors increased 1,25-vitamin D production and renal Cyp27b1 mRNA expression in mice and in human embryonic stem cell–derived kidney organoids. Global- and kidney-specific Sik2/Sik3 mutant mice showed Cyp27b1 upregulation, elevated serum 1,25-vitamin D, and PTH-independent hypercalcemia. The SIK substrate CRTC2 showed PTH and SIK inhibitor–inducible binding to key Cyp27b1 regulatory enhancers in the kidney, which were also required for SIK inhibitors to increase Cyp27b1 in vivo. Finally, in a podocyte injury model of chronic kidney disease–mineral bone disorder (CKD-MBD), SIK inhibitor treatment stimulated renal Cyp27b1 expression and 1,25-vitamin D production. Together, these results demonstrated a PTH/SIK/CRTC signaling axis in the kidney that controls Cyp27b1 expression and 1,25-vitamin D synthesis. These findings indicate that SIK inhibitors might be helpful for stimulation of 1,25-vitamin D production in CKD-MBD.

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Novel strategy of senescence elimination via toxicity-exempted kinome perturbations by nanoliposome-based thermosensitive hydrogel for osteoarthritis therapy

Wan

Zhao

et al. 2023

Adv Compos Hybrid Mater

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Cellular senescence and the senescence-associated secretory phenotype (SASP) have been implicated in osteoarthritis (OA). This study aims to determine whether multi-kinase inhibitor YKL-05-099 (Y099) has potential in senescence elimination and OA therapy and whether delivering Y099 by nanoliposmal hydrogel improves the performance of the kinase inhibitor. Y099 inhibited IL-1β-induced inflammation and catabolism and promoted anabolism of chondrocytes. To attenuate the inhibition of cell viability, nanoliposomal Y099-loaded thermosensitive hydrogel (Y099-Lip-Gel) was developed for sustained release and toxicity exemption. Notably, Y099-Lip-Gel exhibited a pronounced effect on promoting anabolism and suppressing catabolism and inflammation without causing the inhibition of chondrocyte viability. Moreover, Y099-Lip-Gel remarkably increased the master regulator of chondrocyte phenotype Sox9 expression. After four intra-articular injections of Y099-Lip-Gel in the OA murine model, the histological lesions of cartilage were attenuated by Y099-Lip-Gel with subchondral bone loss and osteoclast formation inhibited. Transcriptomic analysis and experimental validations revealed that Y099-Lip-Gel suppressed cellular senescence by inhibiting the expression of senescence inducers and SASP factors. Furthermore, the phosphoproteomic analysis showed that Y099-Lip-Gel exerted a significant influence on kinome phosphorylation, inhibiting the MAPK and NF-κB signaling activations. The protective effects of Y099-Lip-Gel were also validated in cultured human OA cartilage explants. In conclusion, nanoliposomal Y099-loaded thermosensitive hydrogel has considerable potential in OA therapy. Nanoliposome-based hydrogel system has strength in reducing kinase inhibition-induced cytotoxicity, enhancing cellular tolerance to kinome perturbation, and improving the performance of protein kinase inhibitors. Senescence elimination via toxicity-exempted kinome perturbations achieved by advanced nanotechnology is a promising strategy for OA. Graphical Abstract

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Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption

Cited by 12 publications

References 85 publications

Salt-inducible kinase inhibition promotes the adipocyte thermogenic program and adipose tissue browning

Salt-inducible kinase inhibition promotes the adipocyte thermogenic program and adipose tissue browning

A parathyroid hormone/salt-inducible kinase signaling axis controls renal vitamin D activation and organismal calcium homeostasis

Novel strategy of senescence elimination via toxicity-exempted kinome perturbations by nanoliposome-based thermosensitive hydrogel for osteoarthritis therapy

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