小鼠前成骨细胞中的 Pten 基因敲除导致骨转换和骨强度发生变化

IF 3.4 Q2 ENDOCRINOLOGY & METABOLISM JBMR Plus Pub Date : 2024-01-04 DOI:10.1093/jbmrpl/ziad016
J. Lorenz, Sandy Richter, Anna S. Kirstein, Florentien Kolbig, Michèle Nebe, Marco Schulze, Wieland Kiess, Ingo Spitzbarth, Nora Klöting, D. Le Duc, Ulrike Baschant, A. Garten
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引用次数: 0

摘要

骨骼的发育和重塑受磷酸肌醇-3-激酶(Pi3k)信号通路的控制。我们研究了下调磷酸酶和天丝蛋白同源物(Pten)的影响,Pten是Pi3k信号传导的负调控因子。我们的目的是找出参与调节骨转换并与骨疾病相关的机制。我们将从 Osterix/Sp7 表达骨生成细胞中条件性缺失 Pten(Pten cKO)的小鼠体内分离出的股骨、胫骨和骨髓基质细胞(BMSCs)与 Cre 阴性对照组进行了比较。通过μCT测量、骨组织形态测量、骨转换标记物CTX和P1NP定量以及三点弯曲试验对骨表型进行了分析。BMSCs 的增殖通过细胞核计数和 Ki-67 染色细胞进行测量。在体外,通过ALP染色和检测成骨标志物的基因表达来确定成骨分化能力。Pten cKO 小鼠的 BMSCs 在功能上与对照组 BMSCs 不同。Pten cKO 小鼠的 BMSCs 中成骨细胞标志物增加,而 Pten 蛋白表达降低,Akt 磷酸化增加。我们在 Pten cKO 小鼠骨骼中检测到较高的骨小梁体积和改变的皮质骨形态,骨和组织矿物质密度逐渐降低。Pten cKO骨骼的每个骨小梁表面显示出较少的破骨细胞和较多的成骨细胞(p = 0.00095),骨小梁骨形成率较高。生物力学分析表明,Pten cKO 股骨的骨强度(男性 p = 0.00012)和弹性明显更高。在细胞水平上,与对照组相比,Pten cKO BMSCs 的增殖和成骨分化能力均显著提高。我们的研究结果表明,骨生成细胞中的Pten基因敲除可通过增加骨小梁质量来提高骨的稳定性和弹性,并导致骨髓基质细胞的增殖和成骨分化能力增强。
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Pten knockout in mouse preosteoblasts leads to changes in bone turnover and strength
Bone development and remodeling are controlled by the phosphoinositide-3-kinase (Pi3k) signaling pathway. We investigated the effects of downregulation of phosphatase and tensin homolog (Pten), a negative regulator of Pi3k signaling, in a mouse model of Pten deficiency in preosteoblasts. We aimed to identify mechanisms that are involved in the regulation of bone turnover and are linked to bone disorders. Femora, tibiae, and bone marrow stromal cells (BMSCs) isolated from mice with a conditional deletion of Pten (Pten cKO) in Osterix/Sp7 expressing osteoprogenitor cells were compared to Cre negative controls. Bone phenotyping was performed by μCT measurements, bone histomorphometry, quantification of bone turnover markers CTX and P1NP and 3-point bending test. Proliferation of BMSCs was measured by counting nuclei and Ki-67-stained cells. In vitro, osteogenic differentiation capacity was determined by ALP staining, as well as by detecting gene expression of osteogenic markers. BMSCs from Pten cKO mice were functionally different from control BMSCs. Osteogenic markers were increased in BMSCs derived from Pten cKO mice, while Pten protein expression was lower and Akt phosphorylation was increased. We detected a higher trabecular bone volume and an altered cortical bone morphology in Pten cKO bones with a progressive decrease in bone and tissue mineral density. Pten cKO bones displayed fewer osteoclasts and more osteoblasts (p = 0.00095) per trabecular bone surface and a higher trabecular bone formation rate. Biomechanical analysis revealed a significantly higher bone strength (p = 0.00012 for males) and elasticity of Pten cKO femora. On the cellular level, both proliferation and osteogenic differentiation capacity of Pten cKO BMSCs were significantly increased compared to controls. Our findings suggest that Pten knockout in osteoprogenitor cells increases bone stability and elasticity by increasing trabecular bone mass and leads to increased proliferation and osteogenic differentiation of bone marrow stromal cells.
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来源期刊
JBMR Plus
JBMR Plus Medicine-Orthopedics and Sports Medicine
CiteScore
5.80
自引率
2.60%
发文量
103
审稿时长
8 weeks
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