Lv Yongshuang, Zhang Xin, Lu Qizhen, Zhou Yi, Wang Weiyi, Yang Maosheng, Yuan Tao, Liu Yikai, Sun Shui, Li Ziqing
Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Orthopaedic Research Laboratory, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
J Cell Mol Med. 2025 Aug;29(15):e70777. doi: 10.1111/jcmm.70777.
Postmenopausal osteoporosis is primarily attributed to the hyperactivation of osteoclast-induced bone resorption. The differentiation and function of osteoclasts rely on the regulation of calcium oscillations/calcineurin/nuclear factor of activated T cells (Nfat) pathway. Therefore, the development of natural compounds that aim at the crucial regulator of the aforementioned pathway is essential for the suppression of osteoclastogenesis and its clinical application. Skimmianine (Ski), a furoquinoline alkaloid extracted from the Zanthoxylum genus, is known for its anti-inflammatory properties. Yet, its exact role in osteoclast differentiation and function remains largely undefined. Herein, we evaluate the impact of Ski on osteoclastogenesis and elucidate the molecular mechanism involved. We conducted network pharmacology and molecule structure-based pharmacokinetics analyses on Ski, followed by experimental validations on osteoclastogenesis in vitro and ovariectomy (OVX) mice model in vivo. The network pharmacology results indicated Ski's therapeutic effects predominantly influence the calcium signalling pathway by controlling cytosolic calcium concentration in response to bone resorption during osteoporosis. Pharmacokinetic analyses revealed Ski's excellent oral bioavailability. Furthermore, experimental validations revealed that Ski inhibited the formation of multinucleated osteoclasts in a concentration-dependent manner without affecting cell viability, while impeding osteoclast-related gene expression. The underlying mechanism involved the Ski-induced downregulation of calcineurin/Nfatc1 expression through modulation of ERp57-driven calcium oscillations. Micro-CT results confirmed that Ski treatment substantially curbed the progression of osteoporosis by mitigating bone loss. In conclusion, our findings indicated that Ski suppressed osteoclast formation by suppressing ERp57-driven calcium oscillations/calcineurin/Nfatc1 signalling, thus establishing Ski as a promising therapeutic alternative for osteoporosis.
绝经后骨质疏松症主要归因于破骨细胞诱导的骨吸收过度激活。破骨细胞的分化和功能依赖于钙振荡/钙调神经磷酸酶/活化T细胞核因子（Nfat）途径的调节。因此，开发针对上述途径关键调节因子的天然化合物对于抑制破骨细胞生成及其临床应用至关重要。Skimmianine（Ski）是一种从花椒属植物中提取的呋喃喹啉生物碱，以其抗炎特性而闻名。然而，其在破骨细胞分化和功能中的确切作用仍 largely 未明确。在此，我们评估了 Ski 对破骨细胞生成的影响，并阐明了其中涉及的分子机制。我们对 Ski 进行了网络药理学和基于分子结构的药代动力学分析，随后在体外破骨细胞生成和体内卵巢切除（OVX）小鼠模型上进行了实验验证。网络药理学结果表明，Ski 的治疗作用主要通过在骨质疏松症期间控制胞质钙浓度以响应骨吸收来影响钙信号通路。药代动力学分析显示 Ski 具有出色的口服生物利用度。此外，实验验证表明，Ski 以浓度依赖性方式抑制多核破骨细胞的形成，而不影响细胞活力，同时阻碍破骨细胞相关基因的表达。潜在机制涉及 Ski 通过调节 ERp57 驱动的钙振荡诱导钙调神经磷酸酶/Nfatc1 表达的下调。显微CT结果证实，Ski 治疗通过减轻骨质流失显著抑制了骨质疏松症的进展。总之，我们的研究结果表明，Ski 通过抑制 ERp57 驱动的钙振荡/钙调神经磷酸酶/Nfatc1 信号传导来抑制破骨细胞形成，从而确立 Ski 作为一种有前途的骨质疏松症治疗替代品。
