Musculoskeletal Disease Area, Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland.
J Bone Miner Res. 2012 Feb;27(2):360-73. doi: 10.1002/jbmr.1492.
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.
肌细胞增强因子 2（MEF2）是体外成骨细胞骨形成抑制剂 Sost 表达所必需的，暗示这些转录因子在骨生物学中发挥作用。在这里，我们分析了雄性和雌性小鼠在骨骼生长和衰老过程中成骨细胞中 Mef2c 的体内功能。Dmp1-Cre 诱导的 Mef2c 缺陷导致 3.5 个月和 5 至 6 个月龄时股骨皮质骨中 Sost 表达分别降低 40%和 70%。从 2 至 3 个月起，Mef2c 突变体相对于对照小鼠，四肢和轴骨的骨量增加。皮质厚度和长骨及椎体小梁密度升高。为了评估增加的骨量是否与 Sost 表达降低有关，我们对 4 个月大的杂合 Sost 缺陷型小鼠进行了特征描述。Sost 杂合子的长骨骨量和密度增加与 Mef2c 突变体相似，但轴向骨骼参数的相对增加大多较小。在细胞水平上，3.5 月龄 Mef2c 突变鼠的骨形成参数正常，但骨吸收参数显著降低。相应地，Mef2c 突变雄性鼠皮质表达抗破骨细胞生成因子和 Wnt/β-catenin 靶基因骨保护素（OPG）增加 70%。此外，两种性别中 Wnt 信号调节剂 Sfrp2 和 Sfrp3 的皮质表达均强烈失调。相比之下，杂合 Sost 缺陷雄性鼠的成骨细胞矿化速率轻度增加，但破骨细胞表面和包括 OPG 在内的破骨细胞生成调节剂的皮质表达正常，Sfrp2 和 Sfrp3 没有明显变化。综上所述，我们的数据表明 Mef2c 调节皮质 Sfrp2 和 Sfrp3 的表达，并维持体内正常的 Sost 表达。然而，Mef2c 突变体增加的骨量表型与 Sost 表达降低没有直接关系。我们发现 Mef2c 通过调节破骨细胞骨吸收在控制成年骨量方面具有新的功能。
