Bone dysplasia in Hutchinson-Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations.
Bone dysplasia in Hutchinson-Gilford progeria syndrome is associated with dysregulated differentiation and function of bone cell populations.
复制标题
DOI：
10.1111/acel.13903
复制
发表时间：
2023-09
期刊：
影响因子：
7.8
通讯作者：
Collins, Francis S.
中科院分区：
文献类型：
--
作者：
Cabral, Wayne A.;Stephan, Chris;Terajima, Masahiko;Thaivalappil, Abhirami A.;Blanchard, Owen;Tavarez, Urraca L.;Narisu, Narisu;Yan, Tingfen;Wincovitch, Stephen M.;Taga, Yuki;Yamauchi, Mitsuo;Kozloff, Kenneth M.;Erdos, Michael R.;Collins, Francis S.
哈钦森-吉尔福德早衰综合症（HGPS）是一种影响间充质来源组织的过早衰老疾病。大多数患有 HGPS 的个体在编码核纤层蛋白 A (LMNA) 的基因中含有从头 c.1824C > T (p.G608G) 突变，该突变会激活一个隐秘的剪接供体位点，从而产生有毒的“早老素”蛋白。临床表现包括生长缺陷、脂肪营养不良、真皮硬化、心血管缺陷和骨发育不良。在这里，我们利用 HGPS 的 Lmna G609G 敲入 (KI) 小鼠模型来进一步定义与正常和过早衰老疾病相关的骨质流失机制。 KI 小鼠的新生骨骼染色显示，肋骨形状和脊柱弯曲发生改变，颅骨矿化延迟，颅面和下颌软骨含量增加。对成人股骨的 MicroCT 分析和机械测试表明，脆性增加与骨量减少相关，概括了 HGPS 患者发生的进行性骨质恶化。我们在骨细胞群的细胞水平上研究了 KI 小鼠骨质流失的机制。体外 KI 成骨细胞条件培养基抑制来自骨髓源性前体的野生型和 KI 破骨细胞的形成，这表明体内 KI 小梁表面破骨细胞减少的原因是分泌因子。与野生型相比，培养的 KI 成骨细胞表现出异常分化，其特征是细胞外基质沉积和矿化减少，脂质积累增加，从而提供了改变骨形成的机制。此外，KI 转录本的定量分析证实了体外和体内脂肪形成基因的上调。因此，成骨细胞表型可塑性、炎症和细胞串扰的改变导致 HGPS 小鼠骨形成异常。哈钦森-吉尔福德早衰综合症通常被称为一种过早衰老疾病，其特征是动脉粥样硬化、脂肪营养不良和骨质疏松症。在这里，我们证明骨表型是由异常的成骨细胞分化和骨细胞群之间的相互作用改变导致的，导致骨形成和周转率低，这与老年骨质疏松症不同，更准确地描述为骨软骨发育不良。
Hutchinson‐Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo c.1824C > T (p.G608G) mutation in the gene encoding lamin A (LMNA), which activates a cryptic splice donor site resulting in production of the toxic “progerin” protein. Clinical manifestations include growth deficiency, lipodystrophy, sclerotic dermis, cardiovascular defects, and bone dysplasia. Here we utilized the Lmna G609G knock‐in (KI) mouse model of HGPS to further define mechanisms of bone loss associated with normal and premature aging disorders. Newborn skeletal staining of KI mice revealed altered rib cage shape and spinal curvature, and delayed calvarial mineralization with increased craniofacial and mandibular cartilage content. MicroCT analysis and mechanical testing of adult femurs indicated increased fragility associated with reduced bone mass, recapitulating the progressive bone deterioration that occurs in HGPS patients. We investigated mechanisms of bone loss in KI mice at the cellular level in bone cell populations. Formation of wild‐type and KI osteoclasts from marrow‐derived precursors was inhibited by KI osteoblast‐conditioned media in vitro, suggesting a secreted factor(s) responsible for decreased osteoclasts on KI trabecular surfaces in vivo. Cultured KI osteoblasts exhibited abnormal differentiation characterized by reduced deposition and mineralization of extracellular matrix with increased lipid accumulation compared to wild‐type, providing a mechanism for altered bone formation. Furthermore, quantitative analyses of KI transcripts confirmed upregulation of adipogenic genes both in vitro and in vivo. Thus, osteoblast phenotypic plasticity, inflammation and altered cellular cross‐talk contribute to abnormal bone formation in HGPS mice. Hutchinson‐Gilford progeria syndrome is commonly referred to as a premature aging disorder characterized by development of atherosclerosis, lipodystrophy, and osteoporosis. Here we demonstrate that the bone phenotype results from abnormal osteoblast differentiation and altered interactions between bone cell populations leading to a low bone formation and turnover condition, distinct from senile osteoporosis, and more accurately described as an osteochondrodysplasia.
登录
查看更多内容
针对Hutchinson-Gilford Progeria综合征的有针对性的反义治疗方法。
影响因子：
82.9
作者：
Erdos, Michael R.;Cabral, Wayne A.;Tavarez, Urraca L.;Cao, Kan;Gvozdenovic-Jeremic, Jelena;Narisu, Narisu;Zerfas, Patricia M.;Crumley, Stacy;Boku, Yoseph;Hanson, Gunnar;Mourich, Dan V.;Kole, Ryszard;Eckhaus, Michael A.;Gordon, Leslie B.;Collins, Francis S.
通讯作者：
Collins, Francis S.
影响因子：
17.1
作者：
Osorio, Fernando G.;Navarro, Claire L.;Lopez-Otin, Carlos
通讯作者：
Lopez-Otin, Carlos
DOI：
10.1073/pnas.192460799
发表时间：
2002-10-01
影响因子：
11.1
作者：
Bergo, MO;Gavino, B;Young, SG
通讯作者：
Young, SG
影响因子：
11.8
作者：
Hernandez, Lidia;Roux, Kyle J.;Stewart, Colin L.
通讯作者：
Stewart, Colin L.
影响因子：
7.8
作者：
Cabral WA;Tavarez UL;Beeram I;Yeritsyan D;Boku YD;Eckhaus MA;Nazarian A;Erdos MR;Collins FS
通讯作者：
Collins FS