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RUNX2对于维持骺软骨联合软骨细胞和颅底生长至关重要。

RUNX2 is essential for maintaining synchondrosis chondrocytes and cranial base growth.

作者信息

Hallett Shawn A, Dixon Ashley, Marrale Isabella, Batoon Lena, Brenes José, Zhou Annabelle, Arbiv Ariel, Kaartinen Vesa, Allen Benjamin, Ono Wanida, Franceschi Renny T, Ono Noriaki

机构信息

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.

Department of Biological and Materials Sciences and Prosthodontics, University of Michigan School of Dentistry, Ann Arbor, MI, USA.

出版信息

Bone Res. 2025 May 29;13(1):57. doi: 10.1038/s41413-025-00426-z.

DOI:10.1038/s41413-025-00426-z
PMID:40442075
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12122814/
Abstract

The cranial base synchondroses, comprised of opposite-facing bidirectional chondrocyte layers, drive anteroposterior cranial base growth. In humans, RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with deficient midfacial growth. However, how RUNX2 regulates chondrocytes in the cranial base synchondroses remains unknown. To address this, we inactivated Runx2 in postnatal synchondrosis chondrocytes using a tamoxifen-inducible Fgfr3-creER (Fgfr3-Runx2) mouse model. Fgfr3-Runx2 mice displayed skeletal dwarfism and reduced anteroposterior cranial base growth associated with premature synchondrosis ossification due to impaired chondrocyte proliferation, accelerated hypertrophy, apoptosis, and osteoclast-mediated cartilage resorption. Lineage tracing reveals that Runx2-deficient Fgfr3 cells failed to differentiate into osteoblasts. Notably, Runx2-deficient chondrocytes showed an elevated level of FGFR3 and its downstream signaling components, pERK1/2 and SOX9, suggesting that RUNX2 downregulates FGFR3 in the synchondrosis. This study unveils a new role of Runx2 in cranial base chondrocytes, identifying a possible RUNX2-FGFR3-MAPK-SOX9 signaling axis that may control cranial base growth.

摘要

颅底软骨结合由相对的双向软骨细胞层组成，驱动颅底的前后生长。在人类中，RUNX2单倍体不足会导致与面中部生长不足相关的锁骨颅骨发育不全。然而，RUNX2如何调节颅底软骨结合中的软骨细胞仍不清楚。为了解决这个问题，我们使用他莫昔芬诱导的Fgfr3-creER（Fgfr3-Runx2）小鼠模型在出生后软骨结合软骨细胞中使Runx2失活。Fgfr3-Runx2小鼠表现出骨骼矮小，颅底前后生长减少，这与软骨细胞增殖受损、肥大加速、细胞凋亡以及破骨细胞介导的软骨吸收导致的软骨结合过早骨化有关。谱系追踪显示，缺乏Runx2的Fgfr3细胞无法分化为成骨细胞。值得注意的是，缺乏Runx2的软骨细胞显示出FGFR3及其下游信号成分pERK1/2和SOX9水平升高，这表明RUNX2在软骨结合中下调FGFR3。这项研究揭示了Runx2在颅底软骨细胞中的新作用，确定了一个可能控制颅底生长的RUNX2-FGFR3-MAPK-SOX9信号轴。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/2462d2b6aa28/41413_2025_426_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/2bc57b898d73/41413_2025_426_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/e3ecc3881c5b/41413_2025_426_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/4a66bbb8beb9/41413_2025_426_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/a355501c42ba/41413_2025_426_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/7178066feb5e/41413_2025_426_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/779a23dd0acf/41413_2025_426_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/add4628631be/41413_2025_426_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/b243d5c41d00/41413_2025_426_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/2462d2b6aa28/41413_2025_426_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/2bc57b898d73/41413_2025_426_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/e3ecc3881c5b/41413_2025_426_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/4a66bbb8beb9/41413_2025_426_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/a355501c42ba/41413_2025_426_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/7178066feb5e/41413_2025_426_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/779a23dd0acf/41413_2025_426_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/add4628631be/41413_2025_426_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/b243d5c41d00/41413_2025_426_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2be5/12122814/2462d2b6aa28/41413_2025_426_Fig9_HTML.jpg

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Bone Res. 2025-5-29

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

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The Multifaceted Role of miR-211 in Health and Disease.

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本文引用的文献

[1]
Runx2 deletion in hypertrophic chondrocytes impairs osteoclast mediated bone resorption.

Bone. 2024-4

[2]
Bone marrow endosteal stem cells dictate active osteogenesis and aggressive tumorigenesis.

Nat Commun. 2023-4-25

[3]
Inhibition of miR338 rescues cleidocranial dysplasia in Runx2 mutant mice partially via the Hif1a-Vegfa axis.

Exp Mol Med. 2023-1

[4]
Sex Differences in Comorbidities of Pediatric Craniosynostosis at Presentation.

Pediatr Neurosurg. 2023

[5]
The fate of early perichondrial cells in developing bones.

Nat Commun. 2022-11-28

[6]
Cranial Base Synchondrosis: Chondrocytes at the Hub.

Int J Mol Sci. 2022-7-15

[7]
Physiologic Timeline of Cranial-Base Suture and Synchondrosis Closure.

Plast Reconstr Surg. 2021-12-1

[8]
The hypertrophic chondrocyte: To be or not to be.

Histol Histopathol. 2021-10

[9]
Interactions between extracellular signal-regulated kinase 1/2 and P38 MAP kinase pathways in the control of RUNX2 phosphorylation and transcriptional activity.

J Bone Miner Res. 2021-10

[10]
SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation.

Proc Natl Acad Sci U S A. 2021-2-23

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