n-acetyl-l-cysteine stimulates bone healing by recovering the age-associated degenerative complications relative to osteoblastic Wntless ablation

Sher Bahadur Poudel; Min-Hye Kim; Govinda Bhattarai; Han-Sol So; Sung-Ho Kook; Jeong-Chae Lee

doi:10.1016/j.biopha.2024.117761

n-acetyl-l-cysteine stimulates bone healing by recovering the age-associated degenerative complications relative to osteoblastic Wntless ablation

Biomed Pharmacother. 2024 Dec 18:182:117761. doi: 10.1016/j.biopha.2024.117761. Online ahead of print.

Authors

Sher Bahadur Poudel¹, Min-Hye Kim², Govinda Bhattarai³, Han-Sol So², Sung-Ho Kook⁴, Jeong-Chae Lee⁵

Affiliations

¹ Department of Basic Science & Craniofacial Biology, College of Dentistry, New York University, New York, NY 10010, USA.
² Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, South Korea.
³ Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, School of Dentistry, Jeonbuk National University, Jeonju 54896, South Korea.
⁴ Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, South Korea; Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, School of Dentistry, Jeonbuk National University, Jeonju 54896, South Korea. Electronic address: kooksh@jbnu.ac.kr.
⁵ Department of Bioactive Material Sciences, Research Center of Bioactive Materials, Jeonbuk National University, Jeonju 54896, South Korea; Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, School of Dentistry, Jeonbuk National University, Jeonju 54896, South Korea. Electronic address: jeongchae@jbnu.ac.kr.

PMID: 39700869
DOI: 10.1016/j.biopha.2024.117761

Abstract

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^fl/fl mutant and littermate control (Wls^fl/fl) 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^fl/fl 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.

Keywords: Antioxidant therapy; Bone marrow; N-Acetyl-l-cysteine; Osteoblastic Wnts; Oxidative complication; Regenerative bone healing.