A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 08 2022
16 08 2022
Historique:
received:
11
04
2021
accepted:
26
07
2022
entrez:
16
8
2022
pubmed:
17
8
2022
medline:
19
8
2022
Statut:
epublish
Résumé
Brain-derived neurotrophic factor (BDNF) and its tropomyosin-related kinase B receptor (TrkB) are expressed in human osteoblasts and mediate fracture healing. BDNF/TrkB signaling activates Akt that phosphorylates and inhibits asparagine endopeptidase (AEP), which regulates the differentiation fate of human bone marrow stromal cells (hBMSC) and is altered in postmenopausal osteoporosis. Here we show that R13, a small molecular TrkB receptor agonist prodrug, inhibits AEP and promotes bone formation. Though both receptor activator of nuclear factor kappa-Β ligand (RANK-L) and osteoprotegerin (OPG) induced by ovariectomy (OVX) remain comparable between WT and BDNF+/- mice, R13 treatment significantly elevates OPG in both mice without altering RANKL, blocking trabecular bone loss. Strikingly, both R13 and anti-RANK-L exhibit equivalent therapeutic efficacy. Moreover, OVX increases RANK-L and OPG in WT and AEP KO mice with RANK-L/OPG ratio lower in the latter than the former, attenuating bone turnover. 7,8-DHF, released from R13, activates TrkB and its downstream effector CREB, which is critical for OPG augmentation. Consequently, 7,8-DHF represses C/EBPβ/AEP pathway, inhibiting RANK-L-induced RAW264.7 osteoclastogenesis. Therefore, our findings support that R13 exerts its therapeutic efficacy toward osteoporosis via inhibiting AEP and escalating OPG.
Identifiants
pubmed: 35973996
doi: 10.1038/s41467-022-32435-5
pii: 10.1038/s41467-022-32435-5
pmc: PMC9381595
doi:
Substances chimiques
Brain-Derived Neurotrophic Factor
0
Carrier Proteins
0
NF-kappa B
0
Osteoprotegerin
0
Prodrugs
0
RANK Ligand
0
Receptor Activator of Nuclear Factor-kappa B
0
Receptor, trkB
EC 2.7.10.1
Cysteine Endopeptidases
EC 3.4.22.-
asparaginylendopeptidase
EC 3.4.22.34
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4820Subventions
Organisme : NIA NIH HHS
ID : R01 AG065177
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG051538
Pays : United States
Informations de copyright
© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
Références
Cell Res. 2014 Mar;24(3):344-58
pubmed: 24407422
J Med Chem. 2010 Dec 9;53(23):8274-86
pubmed: 21073191
J Biol Chem. 2008 Jun 6;283(23):16259-67
pubmed: 18390540
Mol Metab. 2021 Mar;45:101149
pubmed: 33352311
J Biol Chem. 2014 Oct 3;289(40):27571-84
pubmed: 25143381
Int J Dev Neurosci. 1994 Dec;12(8):685-93
pubmed: 7747595
J Clin Invest. 2016 Jun 1;126(6):2049-63
pubmed: 27111232
Cell Metab. 2015 Nov 3;22(5):799-810
pubmed: 26456334
PLoS One. 2014 Mar 10;9(3):e91453
pubmed: 24614170
J Bone Miner Res. 2007 May;22(5):724-9
pubmed: 17295604
Sci Adv. 2020 Jul 29;6(31):eaba0466
pubmed: 32832679
Endocrinology. 2012 Nov;153(11):5394-405
pubmed: 23011922
Cell Rep. 2019 Jul 16;28(3):655-669.e5
pubmed: 31315045
Curr Opin Neurobiol. 2000 Jun;10(3):381-91
pubmed: 10851172
PLoS One. 2017 Jan 10;12(1):e0169201
pubmed: 28072837
J Biol Chem. 1999 Sep 24;274(39):27747-53
pubmed: 10488118
eNeuro. 2016 Jan 28;3(1):
pubmed: 26839918
J Bone Miner Res. 2013 Jan;28(1):2-17
pubmed: 23197339
J Cell Physiol. 2019 Jul;234(7):11969-11975
pubmed: 30515780
Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10773-10778
pubmed: 28923922
Transl Neurodegener. 2016 Jan 06;5:2
pubmed: 26740873
Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):9094-9102
pubmed: 31004063
Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14574-9
pubmed: 22908268
J Biol Chem. 2003 Aug 29;278(35):33194-9
pubmed: 12775715
Stem Cell Reports. 2017 Feb 14;8(2):373-386
pubmed: 28162997
Neuropsychopharmacology. 2012 Jan;37(2):434-44
pubmed: 21900882
Am J Pathol. 1999 Feb;154(2):405-15
pubmed: 10027399
Ann Anat. 2014 Sep;196(5):286-95
pubmed: 24984919
Neuropsychopharmacology. 2014 Feb;39(3):638-50
pubmed: 24022672
Nat Commun. 2018 May 3;9(1):1784
pubmed: 29725016
J Biol Chem. 2002 Dec 13;277(50):48868-75
pubmed: 12364326
J Clin Invest. 2019 Jul 15;129(8):3018-3028
pubmed: 31305265
Lancet. 2019 Jan 26;393(10169):364-376
pubmed: 30696576
Proc Natl Acad Sci U S A. 2018 Jan 16;115(3):578-583
pubmed: 29295929
Bone Rep. 2015 Jan 21;2:1-7
pubmed: 28377948
J Biol Chem. 1998 Nov 6;273(45):29279-82
pubmed: 9792624
Prog Neurobiol. 2021 Mar;198:101905
pubmed: 32911010
J Bone Miner Res. 2001 Oct;16(10):1804-11
pubmed: 11585344
Chem Biol. 2015 Mar 19;22(3):355-68
pubmed: 25754472
Cell. 2006 Apr 21;125(2):247-60
pubmed: 16630814
Front Cell Neurosci. 2019 Apr 30;13:169
pubmed: 31114483
Gene Ther. 2008 Jan;15(2):109-16
pubmed: 17989700
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3876-81
pubmed: 20133677
Rheumatol Int. 2014 Aug;34(8):1153-7
pubmed: 24399456
Oral Microbiol Immunol. 2009 Oct;24(5):384-9
pubmed: 19702951
Annu Rev Neurosci. 2001;24:677-736
pubmed: 11520916
Biochimie. 2016 Mar;122:126-50
pubmed: 26403494
J Cell Biochem. 2008 Jan 1;103(1):335-45
pubmed: 17516544
Osteoporos Int. 2008 Jan;19(1):1-12
pubmed: 17763997
JCI Insight. 2018 Aug 23;3(16):
pubmed: 30135302
Biochemistry. 1995 Sep 5;34(35):11256-63
pubmed: 7669784