A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin

• Type of Material: Article
• Authors: Jing Xiong, Emory University; Jianming Liao, Emory University; Xia Liu, Emory University; Zhaohui Zhang, Wuhan University; Jonathan Adams, Emory University; Roberto Pacifici, Emory University; Keqiang Ye, Emory University
• Language: English
• Date: 2022-08-16
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-022-32435-5
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 13
• Issue: 1
• Start Page: 4820
• End Page: 4820
• Grant/Funding Information: This work was supported by grants from NIH grant (RF1, AG051538) to K.Y.
• Keywords: RECEPTOR; Science & Technology; EXPRESSION; BETA; NEUROTROPHIC FACTOR; Science & Technology - Other Topics; ACTIVATION; Multidisciplinary Sciences; 7,8-DIHYDROXYFLAVONE; OSTEOCLAST; DELTA-SECRETASE; MEMORY DEFICITS; MOUSE MODEL
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

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.