@article{d573388faf254327b02a865147c88a67,
title = "The role of MEK1/2 and MEK5 in melatonin-mediated actions on osteoblastogenesis, osteoclastogenesis, bone microarchitecture, biomechanics, and bone formation",
abstract = "Melatonin, the primary hormone involved in circadian entrainment, plays a significant role in bone physiology. This study aimed to assess the role of MEK1/2 and MEK5 in melatonin-mediated actions in mouse and human mesenchymal stem cells (MSCs) and on bone using small-molecule inhibitors and CRISPR/Cas9 knockout approaches. Consistent with in vitro studies performed in mMSCs and hMSCs, nightly (25 mg/kg, i.p., 45 days) injections with PD184352 (MEK1/2 inhibitor) or Bix02189 (MEK5 inhibitor) or SC-1-151 (MEK1/2/5 inhibitor) demonstrated that MEK1/2 and MEK5 were the primary drivers underlying melatonin's actions on bone density, microarchitecture (i.e., trabecular number, separation, and connectivity density), and bone mechanical properties (i.e., ultimate stress) through increases in osteogenic (RUNX2, BMP-2, FRA-1, OPG) expression and decreases in PPARγ. Furthermore, CRISPR/Cas9 knockout of MEK1 or MEK5 in mMSCs seeded on PLGA scaffolds and placed into critical-size calvarial defects in Balb(c) mice (male and female) revealed that treatment with melatonin (15 mg/L; p.o., nightly, 90 days) mediates sex-specific actions of MEK1 and MEK5 in new bone formation. This study is the first to demonstrate a role for MEK1/2 and MEK5 in modulating melatonin-mediated actions on bone formation in vivo and in a sex-specific manner.",
keywords = "MAPK, MEK1/2, MEK5, PPARγ, bone mineral density, melatonin, osteoblastogenesis, osteoclastogenesis",
author = "Fahima Munmun and Mohiuddin, {Omair A.} and Hoang, {Van T.} and Burow, {Matthew E.} and Bunnell, {Bruce A.} and Sola, {Veronica M.} and Carpentieri, {Agata R.} and Witt-Enderby, {Paula A.}",
note = "Funding Information: We thank the National Institute for Arthritis and Musculoskeletal Diseases (NIAMS) grant R15 AR068605 awarded to Paula A. Witt-Enderby and the Fulbright Scholarship Commission awarded to Veronica M. Sola, Paula A. Witt-Enderby, and Agata R. Carpentieri. Agata R. Carpentieri is a member of the CONICET scientific researcher career. We also are thankful to Dr. Konstantinos Verdelis (University of Pittsburgh), Dr. Alejandro Almarza (University of Pittsburgh), and Dr. Deborah L. Galson (University of Pittsburgh) for their help with microCT analysis, three-point bending test analysis, and resorption pit analysis, respectively. We would also like to acknowledge Afsin Malik for conducting alizarin red assays testing tryptophan and serotonin in mMSCs. Funding Information: We thank the National Institute for Arthritis and Musculoskeletal Diseases (NIAMS) grant R15 AR068605 awarded to Paula A. Witt‐Enderby and the Fulbright Scholarship Commission awarded to Veronica M. Sola, Paula A. Witt‐Enderby, and Agata R. Carpentieri. Agata R. Carpentieri is a member of the CONICET scientific researcher career. We also are thankful to Dr. Konstantinos Verdelis (University of Pittsburgh), Dr. Alejandro Almarza (University of Pittsburgh), and Dr. Deborah L. Galson (University of Pittsburgh) for their help with microCT analysis, three‐point bending test analysis, and resorption pit analysis, respectively. We would also like to acknowledge Afsin Malik for conducting alizarin red assays testing tryptophan and serotonin in mMSCs. Publisher Copyright: {\textcopyright} 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.",
year = "2022",
month = sep,
doi = "10.1111/jpi.12814",
language = "English",
volume = "73",
journal = "Journal of Pineal Research",
issn = "0742-3098",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "2",
}