Poudel Sher Bahadur, Kim Min-Hye, Bhattarai Govinda, So Han-Sol, Kook Sung-Ho, Lee Jeong-Chae
Department of Basic Science & Craniofacial Biology, College of Dentistry, New York University, New York, NY 10010, USA.
Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, South Korea.
Biomed Pharmacother. 2025 Jan;182:117761. doi: 10.1016/j.biopha.2024.117761. Epub 2024 Dec 18.
Dysregulated Wnt signaling causes age-related characteristics such as oxidative stress, stem cell senescence, and abnormal bone homeostasis. Here we explored whether supplemental n-acetyl-l-cysteine (NAC) recovers the age-associated complications relative to osteoblastic Wntless (Wls) ablation and examined the possible mechanisms therein. For this work, we administered Col2.3-Cre;Wls mutant and littermate control (Wls) mice (14 weeks of age) with NAC (40 mM)-supplemented or NAC-free water for four weeks. A proportion of these mice received non-critical-sized femoral defects at 16 weeks of age. Blood, bone, and bone marrow (BM) samples were collected and adjusted for in vivo, ex vivo, and in vitro analyses. Osteoblastic Wls deletion delayed bone mass accrual and the healing of bone defects, stimulated osteoclastic activation and inflammatory factor expression, and decreased antioxidant enzyme activity in the BM. Osteoblastic Wls deletion also promoted oxidative stress, apoptosis, and senescence in BM stromal cells (BMSCs) and decreased BMSC' multipotencies. Supplementation of Wls mice with NAC enhanced bone mass accrual and regenerative bone healing via a Wnt signal-associated osteogenic activation. However, supplemental NAC induced new bone formation in the mutant mice by inhibiting the age-related complications of BM/BMSCs, as well as by restoring endogenous antioxidant system without any alterations in Wnt ligand secretion, hematopoiesis, and expression of osteogenic and growth factors. This study indicates that supplemental NAC protects mice against Wnt deficiency-mediated and age-associated degenerative complications. Overall, this study highlights the therapeutic potency of NAC for restoring the antioxidant system, stem cell function, and regenerative bone homeostasis in osteoblastic Wls-dispensable manner.
失调的Wnt信号传导会导致与衰老相关的特征，如氧化应激、干细胞衰老和异常的骨稳态。在此，我们探讨了补充N-乙酰-L-半胱氨酸（NAC）是否能恢复与成骨细胞无翅型（Wls）缺失相关的衰老并发症，并研究其中可能的机制。在本研究中，我们给14周龄的Col2.3-Cre;Wls突变小鼠和同窝对照（Wls）小鼠饮用补充了NAC（40 mM）或不含NAC的水，持续四周。这些小鼠中的一部分在16周龄时接受非临界尺寸的股骨缺损手术。收集血液、骨骼和骨髓（BM）样本，用于体内、体外和离体分析。成骨细胞Wls缺失会延迟骨量积累和骨缺损愈合，刺激破骨细胞活化和炎症因子表达，并降低BM中的抗氧化酶活性。成骨细胞Wls缺失还会促进BM基质细胞（BMSCs）中的氧化应激、凋亡和衰老，并降低BMSC的多能性。给Wls小鼠补充NAC可通过与Wnt信号相关的成骨激活增强骨量积累和再生性骨愈合。然而，补充NAC通过抑制BM/BMSCs与年龄相关的并发症，以及通过恢复内源性抗氧化系统，在不改变Wnt配体分泌、造血以及成骨和生长因子表达的情况下，诱导突变小鼠形成新骨。本研究表明，补充NAC可保护小鼠免受Wnt缺乏介导的和与年龄相关的退行性并发症的影响。总体而言，本研究突出了NAC以成骨细胞Wls非依赖性方式恢复抗氧化系统、干细胞功能和再生性骨稳态的治疗潜力。
