title: Mef2c deletion in osteocytes results in increased bone mass.
abstract: Myocyte enhancer factors 2 (MEF2) are required for expression of the osteocyte bone formation inhibitor Sost in vitro, implying these transcription factors in bone biology. Here, we analyzed the in vivo function of Mef2c in osteocytes in male and female mice during skeletal growth and aging. Dmp1-Cre-induced Mef2c deficiency led to progressive decreases in Sost expression by 40% and 70% in femoral cortical bone at 3.5 months and 5 to 6 months of age. From 2 to 3 months onward, bone mass was increased in the appendicular and axial skeleton of Mef2c mutant relative to control mice. Cortical thickness and long bone and vertebral trabecular density were elevated. To assess whether the increased bone mass was related to the decreased Sost expression, we characterized 4-month-old heterozygous Sost-deficient mice. Sost heterozygotes displayed similar increases in long bone mass and density as Mef2c mutants, but the relative increases in axial skeletal parameters were mostly smaller. At the cellular level, bone formation parameters were normal in 3.5-month-old Mef2c mutant mice, whereas bone resorption parameters were significantly decreased. Correspondingly, cortical expression of the anti-osteoclastogenic factor and Wnt/β-catenin target gene osteoprotegerin (OPG) was increased by 70% in Mef2c mutant males. Furthermore, cortical expression of the Wnt signaling modulators Sfrp2 and Sfrp3 was strongly deregulated in both sexes. In contrast, heterozygous Sost deficient males displayed mildly increased osteoblastic mineral apposition rate, but osteoclast surface and cortical expression of osteoclastogenic regulators including OPG were normal and Sfrp2 and Sfrp3 were not significantly changed. Together, our data demonstrate that Mef2c regulates cortical Sfrp2 and Sfrp3 expression and is required to maintain normal Sost expression in vivo. Yet, the increased bone mass phenotype of Mef2c mutants is not directly related to the reduced Sost expression. We identified a novel function for Mef2c in control of adult bone mass by regulation of osteoclastic bone resorption.
authors.affiliation: Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland.
authors.forename: Ina
authors.initials: I
authors.lastname: Kramer
authors.forename: Stefan
authors.initials: S
authors.lastname: Baertschi
authors.forename: Christine
authors.initials: C
authors.lastname: Halleux
authors.forename: Hansjoerg
authors.initials: H
authors.lastname: Keller
authors.forename: Michaela
authors.initials: M
authors.lastname: Kneissel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D020029:Base Pairing / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D001862:Bone Resorption / Q000097:blood / Q000473:pathology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D019426:Integrases / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000378:metabolism; D064326:MEF2 Transcription Factors; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D010011:Osteocytes / Q000378:metabolism*; D010641:Phenotype; D014057:Tomography, X-Ray Computed; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D019426:Integrases; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; D008565:Membrane Proteins; D018006:Myogenic Regulatory Factors; D000099274:Frizzled-Related Proteins; C513308:Dmp1 protein, mouse; C578041:Mef2c protein, mouse; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C486030:Sost protein, mouse; C045073:Cre recombinase