Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption.
Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05-099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here, we report that YKL-05-099 increases bone formation in hypogonadal female mice without increasing bone resorption. Postnatal mice with inducible, global deletion of SIK2 and SIK3 show increased bone mass, increased bone formation, and, distinct from the effects of YKL-05-099, increased bone resorption. No cell-intrinsic role of SIKs in osteoclasts was noted. In addition to blocking SIKs, YKL-05-099 also binds and inhibits CSF1R, the receptor for the osteoclastogenic cytokine M-CSF. Modeling reveals that YKL-05-099 binds to SIK2 and CSF1R in a similar manner. Dual targeting of SIK2/3 and CSF1R induces bone formation without concomitantly increasing bone resorption and thereby may overcome limitations of most current anabolic osteoporosis therapies.
Pubmed ID: 34160349 RIS Download
Research resources used in this publication
- GraphPad Prism (RRID:SCR_002798) (software resource)
- NIH Image (RRID:SCR_003073) (software resource)
- FlowJo (RRID:SCR_008520) (software resource)
- C57BL/6J (RRID:IMSR_JAX:000664) (organism)
- B6.Cg-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze/J (RRID:IMSR_JAX:007914) (organism)
- B6.Cg-Ndor1Tg(UBC-cre/ERT2)1Ejb/2J (RRID:IMSR_JAX:008085) (organism)
- B6.Cg-Tg(Pgk1-flpo)10Sykr/J (RRID:IMSR_JAX:011065) (organism)
Additional research tools detected in this publication
Antibodies used in this publication
- RatLaps™ (CTX-I) EIA Kit (RRID:AB_2801265)
- Rat/Mouse PINP EIA Kit (RRID:AB_2801263)
- Anti-rabbit IgG, HRP-linked Antibody (RRID:AB_2099233)
- PE/Cyanine7 anti-mouse Ly-6C (RRID:AB_1732093)
- FITC anti-mouse CD3epsilon (RRID:AB_312670)
- APC anti-mouse/human CD11b (RRID:AB_312794)
- Rabbit Anti-beta-Tubulin Monoclonal Antibody, Unconjugated, Clone 9F3 (RRID:AB_823664)
- p44/42 MAPK (Erk1/2) (137F5) Rabbit mAb (RRID:AB_390779)
- Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (20G11) Rabbit mAb (RRID:AB_331772)
- M-CSF Receptor (D3O9X) XP® Rabbit mAb (RRID:AB_2799725)
- Phospho-M-CSF Receptor (Tyr723) (49C10) Rabbit mAb (RRID:AB_2085229)
- Rabbit Anti-SIK3 Polyclonal Antibody, Unconjugated (RRID:AB_2042747)
- SIK2 (D28G3) Rabbit mAb (RRID:AB_10830063)
Associated grants
- Agency: NIAMS NIH HHS, United States
Id: R01 AR059847 - Agency: NIDDK NIH HHS, United States
Id: R01 DK116716 - Agency: NIAMS NIH HHS, United States
Id: K08 AR067285 - Agency: NIAMS NIH HHS, United States
Id: P30 AR066261 - Agency: NIDDK NIH HHS, United States
Id: R01 DK092590 - Agency: NIDDK NIH HHS, United States
Id: P01 DK011794
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