Enhanced fracture repair in p21−/− mice is mediated through increased callus mineralization

IF 3.9 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone Pub Date : 2026-02-01 Epub Date: 2025-11-18 DOI:10.1016/j.bone.2025.117732

Alexandra Olsen , Priyatha Premnath , Scott Brunet , Leila Larijani , Sarah L. Manske , Leah Ferrie , Neil A. Duncan , Derrick E. Rancourt , Ralph S. Marcucio , Roman Krawetz

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引用次数: 0

Abstract

Fracture healing is a complex, multi-phase process involving mesenchymal progenitor cell (MPC) recruitment, chondrogenesis, osteogenesis and bone remodelling. The cyclin-dependent kinase inhibitor p21 is known to regulate cell cycle progression and has been implicated in tissue regeneration. Here, we investigated the role of p21 in endochondral fracture repair using a transverse tibial fracture model in physiologically normal mice. Prx1CreERT2-GFP;R26RTdtomato mice on C57BL/6 and p21^−/− backgrounds enabled lineage tracing of MPCs. Longitudinal in vivo micro-CT, histological analysis, tissue cytometry and mechanical testing were used to assess callus formation, cellular composition, and mechanical integrity.

Our results demonstrate that p21^−/− mice exhibit enhanced bone regeneration, with significantly higher bone mineral density (BMD) and bone volume fraction (BV/TV) in the fracture callus at 2 and 4 weeks post-fracture (wpf). Histology revealed increased Prx1⁺ cell recruitment, along with greater expression of chondrogenic (Sox9) and osteogenic (BSP) markers in p21^−/− mice at 2wpf. Biomechanical testing showed that despite similar strength, p21^−/− calluses had reduced toughness, suggesting altered matrix remodelling.

Collectively, our findings highlight p21 as a negative regulator of bone regeneration, likely through modulation of MPC recruitment and differentiation. Together, these data suggest therapeutic targeting of p21 may enhance fracture healing and counteract osteoporosis in terms of bone remodelling and repair.

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p21-/-小鼠骨折修复的增强是通过增加骨痂矿化介导的。

骨折愈合是一个复杂的多阶段过程，涉及间充质祖细胞（MPC）募集、软骨形成、成骨和骨重塑。已知周期蛋白依赖性激酶抑制剂p21调节细胞周期进程，并与组织再生有关。本研究采用生理正常小鼠胫骨横骨折模型研究p21在软骨内骨折修复中的作用。Prx1CreERT2-GFP;C57BL/6和p21-/-背景的R26RTdtomato小鼠实现了MPCs的谱系追踪。纵向体内显微ct、组织学分析、组织细胞术和力学测试用于评估愈伤组织的形成、细胞组成和力学完整性。我们的研究结果表明，p21-/-小鼠在骨折后2周和4周（wpf）表现出增强的骨再生，骨折痂的骨矿物质密度（BMD）和骨体积分数（BV/TV）显著提高。组织学显示p21-/-小鼠在2wpf时Prx1+细胞募集增加，同时软骨生成（Sox9）和成骨（BSP）标记物表达增加。生物力学测试显示，尽管强度相似，但p21-/-老茧的韧性降低，表明基质重塑发生了改变。总的来说，我们的研究结果强调p21是骨再生的负调节因子，可能通过调节MPC的募集和分化。综上所述，这些数据表明p21的靶向治疗可以促进骨折愈合，并在骨重塑和修复方面对抗骨质疏松症。

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

Bone 医学-内分泌学与代谢

CiteScore

8.90

自引率

4.90%

发文量

264

审稿时长

30 days

期刊介绍： BONE is an interdisciplinary forum for the rapid publication of original articles and reviews on basic, translational, and clinical aspects of bone and mineral metabolism. The Journal also encourages submissions related to interactions of bone with other organ systems, including cartilage, endocrine, muscle, fat, neural, vascular, gastrointestinal, hematopoietic, and immune systems. Particular attention is placed on the application of experimental studies to clinical practice.