Effects of MEK1/2 and MEK5 Pathway Disruption on Skeletal Phenotypes in Intact Female SCID Mice

Abstract

Many receptor‐mediated cellular processes progress through mitogen‐activated protein kinase (MAPK) signaling pathways, which are initiated by activation of a surface receptor and ultimately lead to a change in cell physiology. Previous research has shown that the influence of melatonin on osteoblast activity is mediated in part through MAPK/ERK kinases (MEK) 1/2 and MEK5. Here we explore the possible effects of MEK 1/2 and MEK5 disruption on the skeletal structure in rodents with diurnal melatonin rhythms. To investigate the influence of MAPK signaling on bone mineral density and trabecular bone phenotypes, one group of SCID mice (SC; n = 4) was injected daily for a period of 30 days with a dual MEK1/2 and MEK5 inhibitor, SC‐1‐151. A second control group (n = 4) was injected daily with DMSO vehicle for the same period. At the end of the experimental period mice were euthanized, and tibiae were dissected free of soft tissues and fixed in formalin. Tibia were scanned at 9.61 μm3 voxel size for subsequent morphometric analyses. Regions of interest were identified on the scans and then analyzed for trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), bone volume fraction (BV/TV), and cortical bone mineral density (BMD) using ImageJ software. Resulting bone phenotypes were analyzed using Bayesian linear models. We found that the SC group showed credibly decreased BV/TV compared to the DMSO controls (Pr[SC < DMSO] = 0.83). However, comparisons of Tb.Th, Tb.Sp, and BMD indicated minimal credible differences between the SC and DMSO treatment groups. Overall, our results suggest that, while previous research has shown that disruption of the MAPK signaling pathway may have a negative effect on osteoblast activity, these effects may result in only subtle changes for trabecular bone phenotypes and no change in cortical bone mineralization. This project provides preliminary results for a larger‐scale project investigating the role of melatonin, MEK1/2, and MEK5 in bone formation.Support or Funding InformationResearch support: University of Missouri School of Medicine, National Institute of Arthritis and Musculoskeletal and Skin DiseasesThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.