Circulating miR-338 Cluster activities on osteoblast differentiation

Potential diagnostic and therapeutic targets for postmenopausal osteoporosis

Chujiao Lin, Shuaitong Yu, Runze Jin, Yao Xiao, Minghui Pan, Fei Pei, Xiaojing Zhu, Huarong Huang, Zunyi Zhang, Shuo Chen, Huan Liu, Zhi Chen

Research output: Contribution to journalArticle

Abstract

MicroRNAs (miRNAs) are the most abundant RNA species found in serum, and recently, several miRNAs have been found to be associated with osteoporosis. However, the development of such associated miRNAs into diagnostic and therapeutic targets remains unaddressed, mostly because of a lack of functional validation. Here, we identified circulating miR-338 associated with postmenopausal osteoporosis, and performed functional validation in vivo and in vitro. Methods: We collected the serum from postmenopausal osteoporosis patients (N=15) and female volunteers of the same age but with normal bone density (N=15) and examined the enrichment of miR-338 cluster. We also confirmed such enrichment using mice subjected to ovariectomy at different stages. We employed primary bone marrow stromal cells from mice and the MC-3T3 cell line along with CRISPR, RNA-seq and ChIP-qPCR to validate the biological function of secreted miR-338 cluster on osteoblastic differentiation and their upstream regulators. Moreover, we generated miR-338 knockout mice and OVX mice injected with an inhibitor against miR-338 cluster to confirm its biological function in vivo. Results: We observed a significant enrichment of miR-338 cluster in postmenopausal osteoporosis patients. Such enrichment was also prominent in serum from mice subjected to ovariectomy and was detected much earlier than bone density decreases revealed by micro-CT. We also confirmed the presence of an estrogen-dependent Runx2/Sox4/miR-338 positive feedback loop that modulated osteoblast differentiation, providing a possible explanation for our clinical findings. Moreover, deletion of the miR-338 cluster or direct intravenous injection of an miR-338 cluster inhibitor significantly prevented osteoporosis after ovariectomy. Conclusion: Circulating miR-338 cluster in the serum could serve as a promising diagnostic and therapeutic target for postmenopausal osteoporosis patients.

Original languageEnglish (US)
Pages (from-to)3780-3797
Number of pages18
JournalTheranostics
Volume9
Issue number13
DOIs
StatePublished - Jan 1 2019

Fingerprint

Postmenopausal Osteoporosis
Osteoblasts
Ovariectomy
MicroRNAs
Serum
Bone Density
Osteoporosis
Clustered Regularly Interspaced Short Palindromic Repeats
RNA
3T3 Cells
Therapeutics
Mesenchymal Stromal Cells
Knockout Mice
Intravenous Injections
Volunteers
Estrogens
Cell Line

Keywords

  • MicroRNA
  • MiR-338 cluster
  • Osteoporosis
  • Runx2

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

Cite this

Circulating miR-338 Cluster activities on osteoblast differentiation : Potential diagnostic and therapeutic targets for postmenopausal osteoporosis. / Lin, Chujiao; Yu, Shuaitong; Jin, Runze; Xiao, Yao; Pan, Minghui; Pei, Fei; Zhu, Xiaojing; Huang, Huarong; Zhang, Zunyi; Chen, Shuo; Liu, Huan; Chen, Zhi.

In: Theranostics, Vol. 9, No. 13, 01.01.2019, p. 3780-3797.

Research output: Contribution to journalArticle

Lin, C, Yu, S, Jin, R, Xiao, Y, Pan, M, Pei, F, Zhu, X, Huang, H, Zhang, Z, Chen, S, Liu, H & Chen, Z 2019, 'Circulating miR-338 Cluster activities on osteoblast differentiation: Potential diagnostic and therapeutic targets for postmenopausal osteoporosis', Theranostics, vol. 9, no. 13, pp. 3780-3797. https://doi.org/10.7150/thno.34493
Lin, Chujiao ; Yu, Shuaitong ; Jin, Runze ; Xiao, Yao ; Pan, Minghui ; Pei, Fei ; Zhu, Xiaojing ; Huang, Huarong ; Zhang, Zunyi ; Chen, Shuo ; Liu, Huan ; Chen, Zhi. / Circulating miR-338 Cluster activities on osteoblast differentiation : Potential diagnostic and therapeutic targets for postmenopausal osteoporosis. In: Theranostics. 2019 ; Vol. 9, No. 13. pp. 3780-3797.
@article{e09e28ad7990441ca9184ae23a51da3a,
title = "Circulating miR-338 Cluster activities on osteoblast differentiation: Potential diagnostic and therapeutic targets for postmenopausal osteoporosis",
abstract = "MicroRNAs (miRNAs) are the most abundant RNA species found in serum, and recently, several miRNAs have been found to be associated with osteoporosis. However, the development of such associated miRNAs into diagnostic and therapeutic targets remains unaddressed, mostly because of a lack of functional validation. Here, we identified circulating miR-338 associated with postmenopausal osteoporosis, and performed functional validation in vivo and in vitro. Methods: We collected the serum from postmenopausal osteoporosis patients (N=15) and female volunteers of the same age but with normal bone density (N=15) and examined the enrichment of miR-338 cluster. We also confirmed such enrichment using mice subjected to ovariectomy at different stages. We employed primary bone marrow stromal cells from mice and the MC-3T3 cell line along with CRISPR, RNA-seq and ChIP-qPCR to validate the biological function of secreted miR-338 cluster on osteoblastic differentiation and their upstream regulators. Moreover, we generated miR-338 knockout mice and OVX mice injected with an inhibitor against miR-338 cluster to confirm its biological function in vivo. Results: We observed a significant enrichment of miR-338 cluster in postmenopausal osteoporosis patients. Such enrichment was also prominent in serum from mice subjected to ovariectomy and was detected much earlier than bone density decreases revealed by micro-CT. We also confirmed the presence of an estrogen-dependent Runx2/Sox4/miR-338 positive feedback loop that modulated osteoblast differentiation, providing a possible explanation for our clinical findings. Moreover, deletion of the miR-338 cluster or direct intravenous injection of an miR-338 cluster inhibitor significantly prevented osteoporosis after ovariectomy. Conclusion: Circulating miR-338 cluster in the serum could serve as a promising diagnostic and therapeutic target for postmenopausal osteoporosis patients.",
keywords = "MicroRNA, MiR-338 cluster, Osteoporosis, Runx2",
author = "Chujiao Lin and Shuaitong Yu and Runze Jin and Yao Xiao and Minghui Pan and Fei Pei and Xiaojing Zhu and Huarong Huang and Zunyi Zhang and Shuo Chen and Huan Liu and Zhi Chen",
year = "2019",
month = "1",
day = "1",
doi = "10.7150/thno.34493",
language = "English (US)",
volume = "9",
pages = "3780--3797",
journal = "Theranostics",
issn = "1838-7640",
publisher = "Ivyspring International Publisher",
number = "13",

}

TY - JOUR

T1 - Circulating miR-338 Cluster activities on osteoblast differentiation

T2 - Potential diagnostic and therapeutic targets for postmenopausal osteoporosis

AU - Lin, Chujiao

AU - Yu, Shuaitong

AU - Jin, Runze

AU - Xiao, Yao

AU - Pan, Minghui

AU - Pei, Fei

AU - Zhu, Xiaojing

AU - Huang, Huarong

AU - Zhang, Zunyi

AU - Chen, Shuo

AU - Liu, Huan

AU - Chen, Zhi

PY - 2019/1/1

Y1 - 2019/1/1

N2 - MicroRNAs (miRNAs) are the most abundant RNA species found in serum, and recently, several miRNAs have been found to be associated with osteoporosis. However, the development of such associated miRNAs into diagnostic and therapeutic targets remains unaddressed, mostly because of a lack of functional validation. Here, we identified circulating miR-338 associated with postmenopausal osteoporosis, and performed functional validation in vivo and in vitro. Methods: We collected the serum from postmenopausal osteoporosis patients (N=15) and female volunteers of the same age but with normal bone density (N=15) and examined the enrichment of miR-338 cluster. We also confirmed such enrichment using mice subjected to ovariectomy at different stages. We employed primary bone marrow stromal cells from mice and the MC-3T3 cell line along with CRISPR, RNA-seq and ChIP-qPCR to validate the biological function of secreted miR-338 cluster on osteoblastic differentiation and their upstream regulators. Moreover, we generated miR-338 knockout mice and OVX mice injected with an inhibitor against miR-338 cluster to confirm its biological function in vivo. Results: We observed a significant enrichment of miR-338 cluster in postmenopausal osteoporosis patients. Such enrichment was also prominent in serum from mice subjected to ovariectomy and was detected much earlier than bone density decreases revealed by micro-CT. We also confirmed the presence of an estrogen-dependent Runx2/Sox4/miR-338 positive feedback loop that modulated osteoblast differentiation, providing a possible explanation for our clinical findings. Moreover, deletion of the miR-338 cluster or direct intravenous injection of an miR-338 cluster inhibitor significantly prevented osteoporosis after ovariectomy. Conclusion: Circulating miR-338 cluster in the serum could serve as a promising diagnostic and therapeutic target for postmenopausal osteoporosis patients.

AB - MicroRNAs (miRNAs) are the most abundant RNA species found in serum, and recently, several miRNAs have been found to be associated with osteoporosis. However, the development of such associated miRNAs into diagnostic and therapeutic targets remains unaddressed, mostly because of a lack of functional validation. Here, we identified circulating miR-338 associated with postmenopausal osteoporosis, and performed functional validation in vivo and in vitro. Methods: We collected the serum from postmenopausal osteoporosis patients (N=15) and female volunteers of the same age but with normal bone density (N=15) and examined the enrichment of miR-338 cluster. We also confirmed such enrichment using mice subjected to ovariectomy at different stages. We employed primary bone marrow stromal cells from mice and the MC-3T3 cell line along with CRISPR, RNA-seq and ChIP-qPCR to validate the biological function of secreted miR-338 cluster on osteoblastic differentiation and their upstream regulators. Moreover, we generated miR-338 knockout mice and OVX mice injected with an inhibitor against miR-338 cluster to confirm its biological function in vivo. Results: We observed a significant enrichment of miR-338 cluster in postmenopausal osteoporosis patients. Such enrichment was also prominent in serum from mice subjected to ovariectomy and was detected much earlier than bone density decreases revealed by micro-CT. We also confirmed the presence of an estrogen-dependent Runx2/Sox4/miR-338 positive feedback loop that modulated osteoblast differentiation, providing a possible explanation for our clinical findings. Moreover, deletion of the miR-338 cluster or direct intravenous injection of an miR-338 cluster inhibitor significantly prevented osteoporosis after ovariectomy. Conclusion: Circulating miR-338 cluster in the serum could serve as a promising diagnostic and therapeutic target for postmenopausal osteoporosis patients.

KW - MicroRNA

KW - MiR-338 cluster

KW - Osteoporosis

KW - Runx2

UR - http://www.scopus.com/inward/record.url?scp=85067014141&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067014141&partnerID=8YFLogxK

U2 - 10.7150/thno.34493

DO - 10.7150/thno.34493

M3 - Article

VL - 9

SP - 3780

EP - 3797

JO - Theranostics

JF - Theranostics

SN - 1838-7640

IS - 13

ER -