Mef2c regulates bone mass through Sost-dependent and -independent mechanisms

Morfin, Cesar; Sebastian, Aimy; Wilson, Stephen P.; Amiri, Beheshta; Murugesh, Deepa K.; Hum, Nicholas R.; Christiansen, Blaine A.; Loots, Gabriela G.

doi:10.1016/j.bone.2023.116976

Title: Mef2c regulates bone mass through Sost-dependent and -independent mechanisms

Journal Article · Thu Nov 30 00:00:00 EST 2023 · Bone

DOI:https://doi.org/10.1016/j.bone.2023.116976· OSTI ID:2315090

Morfin, Cesar ^[1]; Sebastian, Aimy ^[2]; Wilson, Stephen P. ^[2]; Amiri, Beheshta ^[2]; Murugesh, Deepa K. ^[2]; Hum, Nicholas R. ^[2]; Christiansen, Blaine A. ^[3]; Loots, Gabriela G. ^[1]

University of California, Merced, CA (United States); Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); University of California, Davis, CA (United States)
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
University of California, Davis, CA (United States)

We report Mef2c is a transcription factor that mediates key cellular behaviors that promote endochondral ossification and bone formation. Previously, Mef2c has been shown to regulate Sost transcription via its osteocyte-specific enhancer, ECR5, and conditional deletions of Mef2^cfl/fl with either Col1-Cre or Dmp1-Cre produced generalized high bone mass (HBM) consistent with Van Buchem Disease phenotypes. However, Sost^-/-; Mef2^cfl/fl; Dmp1-Cre mice produced a significantly higher bone mass phenotype that Sost-/- alone suggesting that Mef2c modulates bone mass through additional mechanisms, independent of Sost. To identify new Mef2c transcriptional targets important in bone metabolism, we profiled gene expression by single-cell RNA sequencing in subpopulations of cells isolated from Mef2^cfl/fl; Dmp1-Cre and Mef2^cfl/fl; Bglap-Cre femurs, both strains exhibiting similar high bone mass phenotypes. However, we found Mef2cfl/fl; Bglap-Cre to also display a growth plate defect characterized by an expansion of several osteoprogenitor subpopulations. Differential gene expression analysis identified a total of 96 up- and 2434 down- regulated genes in Mef2^cfl/fl; Bglap-Cre and 176 up- and 1041 down- regulated genes in Mef2^cfl/fl; Dmp1-Cre bone cell subpopulations compared to wildtype mice. Mef2c deletion affected the transcriptomes across several cell types including mesenchymal progenitors (MP), osteoprogenitors (OSP), osteoblast (OB), and osteocyte (OCY) subpopulations. Several energy metabolism genes such as Uqcrb, Ndufv2, Ndufs3, Ndufa13, Ndufb9, Ndufb5, Cox6a1, Cox5a, Atp5o, Atp5g2, Atp5b, Atp5 were significantly down regulated in Mef2c-deficient OBs and OCYs, in both strains. Binding motif analysis of promoter regions of differentially expressed genes identified Mef2c binding in Bone Sialoprotein (BSP/Ibsp), a gene known to cause increased trabecular BV/TV in the femurs of Ibsp^-/- mice. Immunohistochemical analysis confirmed the absence of Ibsp protein in OBs and OCYs. These findings suggests that the HBM in Sost^-/-; Mef2^cfl/fl; Dmp1-Cre is caused by a multitude of transcriptional changes in genes that regulate bone formation, two of which are Sost and Ibsp.

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Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH)

Grant/Contract Number:: AC52-07NA27344; R56DK110145

OSTI ID:: 2315090

Report Number(s):: LLNL-JRNL-845815; 1069320

Journal Information:: Bone, Vol. 179, Issue N/A; ISSN 8756-3282

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Mef2c
Sost
Van Buchem disease
osteocyte
osteoblast
Ibsp
high bone mass
scRNA-seq
sclerostin
BSP
Mef2

Title: Mef2c regulates bone mass through Sost-dependent and -independent mechanisms

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