在骨髓刺激大鼠模型中，纤维软骨修复涉及慢性细胞衰老

Osteoarthritis and cartilage open Pub Date : 2025-04-29 DOI:10.1016/j.ocarto.2025.100620

Luke Childress , Landon B. Gatrell , Hong Wu , Elisabeth Ferreira , Intawat Nookaew , Ryan M. Porter

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引用次数: 0

摘要

细胞衰老与创伤后骨关节炎的进展有关，但在骨关节炎前软骨修复中的作用尚不清楚。我们的目的是确定衰老细胞是否有助于骨髓刺激啮齿动物模型的纤维软骨修复。设计在青壮年Lewis大鼠和中年Lewis大鼠滑车沟内制造1 mm骨软骨缺损，模拟人类接受骨髓刺激时的年龄范围。部分大鼠关节内注射抗衰老药物纳维托克或达沙替尼加槲皮素。修复组织在骨髓刺激后的第一个月内通过组织学以及大量和单细胞转录组学分析进行表征。结果与相邻的完整关节软骨相比，在修复后的头几个月，修复组织内测量了多种衰老标志物。IA递送抗衰老药物可减少p16ink4a免疫阳性细胞数量，但不促进软骨形成。尽管蛋白多糖沉积随着年龄的增长而明显减少，但青年和中年大鼠的p16阳性细胞数量相似。修复组织的大量RNA测序显示，与已建立的衰老相关分泌表型相关的因子持续上调。单细胞RNA测序揭示了早期修复组织内间充质细胞的异质性，证实了新形成的软骨细胞与相邻完整软骨内衰老标志物表达的差异，并确定了这两个群体在修复软骨形成阶段氧化应激反应的差异。结论骨髓刺激后的修复组织中存在大量衰老细胞，包括新生软骨细胞。虽然它们的纤维性SASP与愈合不良有关，但在诱导衰老后去除它们并不能改善修复组织的质量，这可能是由于缺乏替代的软骨细胞群。

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Fibrocartilage repair involves chronic cellular senescence in a rat model of bone marrow stimulation

Objective

Cellular senescence has been implicated in the progression of post-traumatic osteoarthritis, but any role in pre-osteoarthritic cartilage repair is unknown. Our objective was to determine whether senescent cells contribute to fibrocartilage repair using a rodent model of marrow stimulation.

Design

A 1 mm osteochondral defect was generated in the trochlear groove of young adult and middle-aged Lewis rats, modeling the age range when humans receive marrow stimulation. Some rats were treated by intra-articular (IA) injection of senolytic drugs navitoclax or dasatinib plus quercetin. Repair tissue was characterized during the first months after marrow stimulation by histology as well as bulk and single cell transcriptomic analysis.

Results

Multiple senescence markers were measured within repair tissue during the first months of repair, in contrast to adjacent, intact articular cartilage. The IA delivery of senolytic drugs reduced p16^Ink4a-immunopositive cell numbers but did not promote chondrogenesis. The numbers of p16-positive cells were similar between young adult and middle-aged rats, despite proteoglycan deposition decreasing markedly with age. Bulk RNA sequencing of repair tissue demonstrated sustained upregulation of factors linked to established forms of the senescence-associated secretory phenotype. Single cell RNA sequencing revealed heterogeneity in mesenchymal cells within the early repair tissue, confirmed differences in senescence marker expression between newly-formed chondrocytes and those within adjacent intact cartilage, and established differences in oxidative stress response between these two populations during the chondrogenic phase of repair.

Conclusions

Senescent cells, including neochondrocytes, are abundant within inferior repair tissue following marrow stimulation. While their fibrogenic SASP is associated with poor healing, their removal after senescence induction does not improve repair tissue quality, possibly due to the lack of a replacement chondrogenic population.

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来源期刊

Osteoarthritis and cartilage open Orthopedics, Sports Medicine and Rehabilitation

CiteScore

3.30

自引率

0.00%

发文量