Loss of the Ubiquitin-Associated Domain of sqstm1/p62 in Zebrafish Causes a Phenotype Resembling Paget's Disease of Bone.

IF 3.3 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM Calcified Tissue International Pub Date : 2025-03-14 DOI:10.1007/s00223-025-01360-2
Yentl Huybrechts, Raphaël De Ridder, Dylan Bergen, Björn De Samber, Eveline Boudin, Francesca Tonelli, Dries Knapen, Lucia Vergauwen, Dorien Schepers, Evelien Van Dijck, Qiao Tong, Anja Verhulst, Jan De Beenhouwer, Jan Sijbers, Chrissy Hammond, Antonella Forlino, Geert Mortier, Paul Coucke, P Eckhard Witten, Ronald Young Kwon, Andy Willaert, Gretl Hendrickx, Wim Van Hul
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Abstract

The ubiquitin-binding protein p62, encoded by Sequestosome 1 (SQSTM1), is an essential molecular adaptor for selective autophagy. Heterozygous mutations deleting or disrupting the ubiquitin-associated (UBA) domain of p62 have been reported as the major genetic cause for Paget's disease of bone (PDB), the second most common skeletal disease, characterized by hyperactive osteoclasts and focal increases of bone turnover. In this study, we aimed to determine the impact of a similar sqstm1/p62 mutation on the skeleton of zebrafish. We successfully established a sqstm1tmΔUBA zebrafish line with premature truncation of the UBA domain and performed skeletal phenotyping of heterozygous and homozygous mutant zebrafish. Homozygous sqstm1tmΔUBA zebrafish suffered from early lethality after 6 mpf, possibly related to a dysregulated autophagy process. Nevertheless, we detected skeletal abnormalities that were generally more severe in older animals and in homozygous versus heterozygous sqstm1tmΔUBA zebrafish. MicroCT analysis and histologic staining showed alterations in the vertebral bodies and/or bone density in heterozygous sqstm1tmΔUBA zebrafish. We also detected signs of osteocytic osteolysis in carriers of a mutant sqstm1tmΔUBA allele, shown by a higher percentage of enlarged osteocyte lacunae at 12mpf (36% in heterozygote mutants, 20% in wild types). By performing scale histomorphometry, we also detected a higher degree of scale resorption in homozygous sqstm1tmΔUBA zebrafish at 6 mpf. In conclusion, we have generated a Sqstm1 mutant zebrafish model with features of PDB, characterized by focal bone defects and increased osteoclast activity. This model may be useful to further define PDB disease mechanisms and other p62-related (patho)physiological processes.

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斑马鱼体内 sqstm1/p62 的泛素相关域缺失会导致类似于骨质疏松症的表型。
泛素结合蛋白 p62 由 Sequestosome 1 (SQSTM1) 编码,是选择性自噬的重要分子适配体。据报道,缺失或破坏 p62 泛素相关(UBA)结构域的杂合突变是导致帕吉特氏骨病(PDB)的主要遗传原因,帕吉特氏骨病是第二大常见骨骼疾病,其特征是破骨细胞亢进和局灶性骨转换增加。在这项研究中,我们旨在确定类似的 sqstm1/p62 突变对斑马鱼骨骼的影响。我们成功建立了UBA结构域过早截断的sqstm1tmΔUBA斑马鱼品系,并对杂合突变斑马鱼和同源突变斑马鱼进行了骨骼表型分析。同基因sqstm1tmΔUBA斑马鱼在6 mpf后出现早期死亡,这可能与自噬过程失调有关。尽管如此,我们还是检测到了骨骼异常,一般来说,年龄较大的动物骨骼异常更为严重,而且同卵与杂合的 sqstm1tmΔUBA 斑马鱼骨骼异常也更为严重。显微CT分析和组织学染色显示,杂合子sqstm1tmΔUBA斑马鱼的椎体和/或骨密度发生了改变。我们还在突变型 sqstm1tmΔUBA 等位基因携带者体内检测到了骨细胞溶解的迹象,表现为 12mpf 处扩大的骨细胞裂隙比例更高(杂合子突变体为 36%,野生型为 20%)。通过鳞片组织形态测定法,我们还检测到同基因sqstm1tmΔUBA斑马鱼在6 mpf时鳞片吸收程度更高。总之,我们生成了一种具有 PDB 特征的 Sqstm1 突变斑马鱼模型,其特征是局灶性骨缺损和破骨细胞活性增加。该模型可能有助于进一步确定 PDB 疾病机制及其他与 p62 相关的(病理)生理过程。
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来源期刊
Calcified Tissue International
Calcified Tissue International 医学-内分泌学与代谢
CiteScore
8.00
自引率
2.40%
发文量
112
审稿时长
4-8 weeks
期刊介绍: Calcified Tissue International and Musculoskeletal Research publishes original research and reviews concerning the structure and function of bone, and other musculoskeletal tissues in living organisms and clinical studies of musculoskeletal disease. It includes studies of cell biology, molecular biology, intracellular signalling, and physiology, as well as research into the hormones, cytokines and other mediators that influence the musculoskeletal system. The journal also publishes clinical studies of relevance to bone disease, mineral metabolism, muscle function, and musculoskeletal interactions.
期刊最新文献
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