Induced pluripotent stem cells from homozygous Runx2-deficient mice show poor response to vitamin D during osteoblastic differentiation
Induced pluripotent stem cells from homozygous Runx2-deficient mice show poor response to vitamin D during osteoblastic differentiation
复制标题
DOI：
10.1007/s00795-022-00317-w
复制
发表时间：
2022-04
影响因子：
1.8
通讯作者：
H. Aoki;E. Suzuki;Takashi Nakamura;Shoko Onodera;A. Saito;M. Ohtaka;M. Nakanishi;K. Nishimura;Atsushi Saito;Toshifumi Azuma
中科院分区：
文献类型：
--
作者：
H. Aoki;E. Suzuki;Takashi Nakamura;Shoko Onodera;A. Saito;M. Ohtaka;M. Nakanishi;K. Nishimura;Atsushi Saito;Toshifumi Azuma
锁骨颅骨发育不良是一种与骨骼发育不良和牙齿畸形相关的遗传性疾病。该病是由Runt相关转录因子2(RUNX2)基因杂合性功能缺失突变引起的。骨质疏松症常见于慢性骨质疏松症患者，建议常规补充维生素D。然而，目前还没有提出足够的证据。本研究探讨了RUNX2在成骨细胞分化中的作用，并试图利用诱导多能干细胞(IPSC)技术寻找潜在的靶向基因，用于治疗与成骨细胞分化相关的骨质疏松症。我们从产仔相配的小鼠中成功地建立了Runx2−/−、Runx2+/−和野生型miPSCs，并发现Runx2−/−细胞中Vdrex表达较弱。在Runx2−/−中观察到成骨细胞分化的显著下调。基因表达阵列显示了意外的结果，如Rank1的表达显著增加，VdrinRunx2的−/−细胞减少。Runx2−/−细胞对维生素D的反应也不充分。我们的结果表明，RUNX2作为Rankland Vdr2的调节器，从而控制骨密度。这些发现还表明，传统的维生素D补充剂在治疗与CCD相关的骨质疏松症方面可能并不像之前预期的那样有效，抑制RANKL功能可能值得考虑作为一种替代治疗策略。
Cleidocranial dysplasia (CCD) is a hereditary disorder associated with skeletal dysplasia and dental abnormalities. CCD arises from heterozygous loss of function mutations in the Runt-related transcription factor 2 (RUNX2) gene. Osteoporosis is often observed in CCD patients and conventional vitamin D supplementation is recommended. However, sufficient evidences have not been presented yet. This study investigated the role of RUNX2 in osteoblastic differentiation and sought to identify potential target genes for the treatment of osteoporosis associated with CCD, using induced pluripotent stem cell (iPSC) technology. We successfully establishedRunx2−/−, Runx2+/−and wild-type miPSCs from litter-matched mice and found poorVdrexpression inRunx2−/−cells. Significant down-regulation of osteoblastic differentiation inRunx2−/−miPSCs was observed. Gene expression array revealed unexpected results such as remarkable increase ofRanklexpression and decrease ofVdrinRunx2−/−cells. Insufficient response to vitamin D inRunx2−/−cells was also observed. Our results suggest that RUNX2 functions as a regulator ofRanklandVdrand thereby controls bone density. These findings also suggest that conventional vitamin D supplementation may not be as effective as previously expected, in the treatment of osteoporosis associated with CCD, and that inhibiting RANKL function might be worth considering as an alternative treatment strategy.