Clearance of Senescent Cells From Injured Muscle Abrogates Heterotopic Ossification in Mouse Models of Fibrodysplasia Ossificans Progressiva.
Clearance of Senescent Cells From Injured Muscle Abrogates Heterotopic Ossification in Mouse Models of Fibrodysplasia Ossificans Progressiva.
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DOI：
10.1002/jbmr.4458
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Pignolo RJ
中科院分区：
文献类型：
--
作者：
Wang H;Zhang Q;Kaplan FS;Pignolo RJ
进行性骨化性纤维发育不良 (FOP) 是一种罕见的遗传性疾病，由 I 型激活素 A 受体/I 型激活素样激酶 2 (ACVR1/ALK2)（一种骨形态发生蛋白 (BMP) I 型受体）突变引起，导致骨外或异位骨化 (HO) 的形成以及与过早衰老相符的其他特征。在生命的第一个十年中，会发生间歇性的炎症肿胀（突发），这通常是由软组织创伤引发的。通过软骨内过程，这些恶化最终导致骨骼肌、肌腱、韧带、筋膜和腱膜转变为异位骨，导致运动变得不可能。我们之前已经表明，软组织损伤会导致早期 FOP 病变，其特征是细胞缺氧、细胞损伤和局部炎症。在这里，我们表明，FOP 中的肌肉损伤也会导致衰老细胞积累，并且衰老会促进组织重编程，以实现 FOP 肌肉中的软骨形成命运，但野生型 (WT) 肌肉则不然。通过联合使用抗衰老药物，我们发现衰老细胞的清除和衰老相关分泌表型 (SASP) 的减少可改善 FOP 小鼠模型中的 HO。我们得出的结论是，损伤诱导的衰老细胞负担和 SASP 有助于 FOP 病变的形成，并且 FOP 中的组织重编程是由细胞衰老介导的，将肌源细胞命运改变为软骨细胞命运。此外，通过药物去除衰老细胞会消除组织重编程和 H2O 形成。在这里，我们提供了 senolytic 药物作为 FOP 未来治疗策略的原理验证证据。
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease caused by mutations in activin A receptor type I/activin-like kinase 2 (ACVR1/ALK2), a bone morphogenetic protein (BMP) type I receptor, resulting in the formation of extraskeletal or heterotopic ossification (HO) and other features consistent with premature aging. During the first decade of life, episodic bouts of inflammatory swellings (flare-ups) occur, which are typically triggered by soft tissue trauma. Through an endochondral process, these exacerbations ultimately result in skeletal muscles, tendons, ligaments, fascia, and aponeuroses transforming into ectopic bone, rendering movement impossible. We have previously shown that soft tissue injury causes early FOP lesions characterized by cellular hypoxia, cellular damage, and local inflammation. Here we show that muscle injury in FOP also results in senescent cell accumulation, and that senescence promotes tissue reprogramming toward a chondrogenic fate in FOP muscle but not wild-type (WT) muscle. Using a combination of senolytic drugs we show that senescent cell clearance and reduction in the senescence associated secretory phenotype (SASP) ameliorate HO in mouse models of FOP. We conclude that injury-induced senescent cell burden and the SASP contribute to FOP lesion formation and that tissue reprogramming in FOP is mediated by cellular senescence, altering myogenic cell fate toward a chondrogenic cell fate. Furthermore, pharmacological removal of senescent cells abrogates tissue reprogramming and HO formation. Here we provide proof-of-principle evidence for senolytic drugs as a future therapeutic strategy in FOP.
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影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
影响因子：
3.7
作者：
Pignolo RJ;Shore EM;Kaplan FS
通讯作者：
Kaplan FS
DOI：
10.18632/aging.101425
发表时间：
2018-04-25
期刊：
Aging
影响因子：
--
作者：
Sugihara H;Teramoto N;Yamanouchi K;Matsuwaki T;Nishihara M
通讯作者：
Nishihara M
影响因子：
17.1
作者：
Hatsell SJ;Idone V;Wolken DM;Huang L;Kim HJ;Wang L;Wen X;Nannuru KC;Jimenez J;Xie L;Das N;Makhoul G;Chernomorsky R;D'Ambrosio D;Corpina RA;Schoenherr CJ;Feeley K;Yu PB;Yancopoulos GD;Murphy AJ;Economides AN
通讯作者：
Economides AN
影响因子：
30.8
作者：
Shore, EM;Xu, MQ;Kaplan, FS
通讯作者：
Kaplan, FS