p21 Inhibition Rescues Radiation-Induced Osteogenic Dysfunction and Promotes Bone Regeneration in Osteoradionecrosis of the Jaw via the Rb-Smad2/3-Runx2 Axis.

IF 3.1 3区医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE

Oral diseases Pub Date : 2026-08-18 DOI:10.1111/odi.70408

Jiaying Shi, Shuxian Lin, Jiayu Yan, Wanyi Tang, Xiaohua Wu, Shuwen Ding, Siyi Chen, Ruowen Zhao, Junhua Wu

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引用次数: 0

Abstract

Background: Osteoradionecrosis of the jaw (ORNJ) is a severe radiotherapy complication with unclear molecular drivers. CDKN1A/p21 is upregulated by radiation-induced DNA damage, but its role in ORNJ remains unknown.

Methods: An ORNJ mouse model was established. Single-cell RNA-sequencing of irradiated mandibles was analyzed and validated in vivo. Irradiated jaw bone marrow mesenchymal stem cells (JBMMSCs) were characterized. p21 was inhibited using UC2288 and siRNA. A UC2288-loaded AlgMA hydrogel was developed for local delivery.

Results: Bone healing was compromised in ORNJ. Radiation induced p21 upregulation in osteogenic lineage cells, which promoted Rb dephosphorylation and aberrant Smad2/3 phosphorylation, thereby suppressing Runx2-mediated osteogenesis. p21 inhibition reversed this cascade and restored osteogenic differentiation. Local delivery of UC2288@AlgMA significantly enhanced bone regeneration.

Conclusion: p21-related signaling impairs bone healing after irradiation, and local UC2288 delivery via AlgMA hydrogels represents a viable strategy to enhance ORNJ regeneration.

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p21抑制通过Rb-Smad2/3-Runx2轴恢复辐射诱导的颌骨骨坏死成骨功能障碍并促进骨再生

背景：颌骨放射性骨坏死（ORNJ）是一种严重的放射治疗并发症，其分子驱动因素尚不清楚。CDKN1A/p21在辐射诱导的DNA损伤中上调，但其在ORNJ中的作用尚不清楚。方法：建立ORNJ小鼠模型。对辐照下颌骨单细胞rna测序进行了体内分析和验证。对辐照颌骨骨髓间充质干细胞（JBMMSCs）进行表征。使用UC2288和siRNA抑制p21。一种uc2288负载的AlgMA水凝胶被开发用于局部递送。结果：ORNJ的骨愈合受到损害。辐射诱导成骨谱系细胞p21上调，促进Rb去磷酸化和Smad2/3异常磷酸化，从而抑制runx2介导的成骨。抑制P21逆转了这一级联反应，恢复了成骨分化。局部给药UC2288@AlgMA可显著促进骨再生。结论：p21相关信号会损害照射后的骨愈合，通过AlgMA水凝胶局部递送UC2288是促进ORNJ再生的可行策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Oral diseases 医学-牙科与口腔外科

CiteScore

7.60

自引率

5.30%

发文量

325

审稿时长

4-8 weeks

期刊介绍： Oral Diseases is a multidisciplinary and international journal with a focus on head and neck disorders, edited by leaders in the field, Professor Giovanni Lodi (Editor-in-Chief, Milan, Italy), Professor Stefano Petti (Deputy Editor, Rome, Italy) and Associate Professor Gulshan Sunavala-Dossabhoy (Deputy Editor, Shreveport, LA, USA). The journal is pre-eminent in oral medicine. Oral Diseases specifically strives to link often-isolated areas of dentistry and medicine through broad-based scholarship that includes well-designed and controlled clinical research, analytical epidemiology, and the translation of basic science in pre-clinical studies. The journal typically publishes articles relevant to many related medical specialties including especially dermatology, gastroenterology, hematology, immunology, infectious diseases, neuropsychiatry, oncology and otolaryngology. The essential requirement is that all submitted research is hypothesis-driven, with significant positive and negative results both welcomed. Equal publication emphasis is placed on etiology, pathogenesis, diagnosis, prevention and treatment.