骨髓脂肪细胞分泌的血清淀粉样蛋白P会引发骨骼淀粉样变性。

Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis.

作者信息

Kumar Surendra, Song Kangping, Wang Jiekang, Baghel Meghraj Singh, Zeng Yixiang, Shen Ke, Zheng Junying, Crane Janet, Demehri Shadpour, Gao Peisong, Jain Amit, Skolasky Richard L, Wong Philip, Cao Xu, Wan Mei

机构信息

Department of Orthopaedic Surgery, the Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Department of Biomedical Engineering, the Johns Hopkins University School of Medicine, Baltimore, MD, USA.

出版信息

Nat Aging. 2025 Jul 29. doi: 10.1038/s43587-025-00924-z.

DOI:10.1038/s43587-025-00924-z

PMID:40730660

Abstract

The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on organ aging. Here, we demonstrate that both transgenic Alzheimer's disease (AD) mice and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits. Senescent BMAds acquire a secretory phenotype, markedly increasing secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAds in vivo and promotes insoluble amyloid formation from soluble amyloid-β (Aβ) peptides in in vitro and ex vivo three-dimensional (3D) BMAd-based cultures. Combined SAP/PTX2 and Aβ treatment promotes osteoclastogenesis but inhibits osteoblastogenesis. Transplanting senescent BMAds into the bone marrow cavity of young mice induces bone loss, which is reversed by senolytic treatment. Finally, depleting SAP/PTX2 in aged mice abolishes marrow amyloid deposition and rescues low bone mass. Thus, senescent BMAds drive age-related skeletal amyloidosis and bone deficits via SAP/PTX2.

摘要

淀粉样纤维的积累已在脑外组织中被发现，但对于脑外淀粉样变性的形成及其对器官衰老的影响却知之甚少。在此，我们证明转基因阿尔茨海默病（AD）小鼠和自然衰老小鼠均表现出衰老的骨髓脂肪细胞（BMAds）积累，并伴有淀粉样沉积物。衰老的BMAds获得分泌表型，显著增加血清淀粉样P成分（SAP，也称为五聚素2，PTX2）的分泌。在体内，SAP/PTX2与衰老BMAds周围的淀粉样沉积物共定位，并在体外和基于BMAds的三维（3D）离体培养中促进可溶性淀粉样β（Aβ）肽形成不溶性淀粉样蛋白。联合使用SAP/PTX2和Aβ处理可促进破骨细胞生成，但抑制成骨细胞生成。将衰老的BMAds移植到年轻小鼠的骨髓腔中会导致骨质流失，而衰老细胞溶解疗法可逆转这种情况。最后，在老年小鼠中消耗SAP/PTX2可消除骨髓淀粉样沉积并挽救低骨量。因此，衰老的BMAds通过SAP/PTX2驱动与年龄相关的骨骼淀粉样变性和骨质缺损。