The nuclear lamina protein lamin A/C is a key component of the nuclear envelope. Mutations in the lamin A/C gene (LMNA) are identified in patients with various types of laminopathy-containing diseases, which have features of accelerated aging and osteoporosis. However, the underlying mechanisms for laminopathy-associated osteoporosis remain largely unclear. Here, we provide evidence that loss of lamin A/C in skeletal muscles, but not osteoblast (OB)-lineage cells, results in not only muscle aging–like deficit but also trabecular bone loss, a feature of osteoporosis. The latter is due in large part to elevated bone resorption. Further cellular studies show an increase of osteoclast (OC) differentiation in cocultures of bone marrow macrophages/monocytes (BMMs) and OBs after treatment with the conditioned medium (CM) from lamin A/C–deficient muscle cells. Antibody array screening analysis of the CM proteins identifies interleukin (IL)-6, whose expression is markedly increased in lamin A/C–deficient muscles. Inhibition of IL-6 by its blocking antibody in BMM-OB cocultures diminishes the increase of osteoclastogenesis. Knockout (KO) of IL-6 in muscle lamin A/C–KO mice diminishes the deficits in trabecular bone mass but not muscle. Further mechanistic studies reveal an elevation of cellular senescence marked by senescence-associated beta-galactosidase (SA-β-gal), p16^Ink4a, and p53 in lamin A/C–deficient muscles and C2C12 muscle cells, and the p16^Ink4a may induce senescence-associated secretory phenotype (SASP) and IL-6 expression. Taken together, these results suggest a critical role for skeletal muscle lamin A/C to prevent cellular senescence, IL-6 expression, hyperosteoclastogenesis, and trabecular bone loss, uncovering a pathological mechanism underlying the link between muscle aging/senescence and osteoporosis.

核纤层蛋白 lamin A/C 是核膜的关键组成部分。核纤层蛋白 A/C 基因突变 ( LMNA) 发现于患有各种类型的椎板病变疾病的患者，这些疾病具有加速衰老和骨质疏松症的特征。然而，椎板病相关骨质疏松症的潜在机制仍不清楚。在这里，我们提供证据表明骨骼肌中核纤层蛋白 A/C 的损失，而不是成骨细胞 (OB) 谱系细胞，不仅会导致肌肉老化样缺陷，还会导致骨小梁丢失，这是骨质疏松症的一个特征。后者在很大程度上是由于骨吸收增加。进一步的细胞研究表明，在用来自核纤层蛋白 A/C 缺陷的肌肉细胞的条件培养基 (CM) 处理后，骨髓巨噬细胞/单核细胞 (BMM) 和 OB 的共培养物中破骨细胞 (OC) 分化增加。CM 蛋白的抗体阵列筛选分析鉴定了白细胞介素 (IL)-6，其表达在核纤层蛋白 A/C 缺乏的肌肉中显着增加。在 BMM-OB 共培养物中通过其阻断抗体抑制 IL-6 可减少破骨细胞生成的增加。肌肉层粘连蛋白 A/C-KO 小鼠中 IL-6 的敲除 (KO) 可减少小梁骨量的缺陷，但不会减少肌肉。进一步的机制研究揭示了以衰老相关的 β-半乳糖苷酶 (SA-β-gal)、p16 为标志的细胞衰老升高^{核纤层蛋白 A/C 缺陷肌肉和 C2C12 肌肉细胞中的Ink4a}和 p53，以及 p16 ^Ink4a可能诱导衰老相关分泌表型 (SASP) 和 IL-6 表达。总之，这些结果表明骨骼肌核纤层蛋白 A/C 在预防细胞衰老、IL-6 表达、高破骨细胞生成和骨小梁丢失方面发挥着关键作用，揭示了肌肉衰老/衰老与骨质疏松症之间联系的病理机制。