Work

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

Year: 2024

Type: article

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. • This study examines a relationship between Wnt signal and NAC-induced bone repair. • Osteoblastic Wls ablation delays bone healing along with functional loss of BM cells. • NAC stimulates bone healing and restores MSC function and antioxidant system. • NAC can improve age-related complications even at the lack of osteoblastic Wnts. • Collectively, this study demonstrates a potency of NAC for antioxidant therapy.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2024.117761

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

Institutions: New York University, Jeonbuk National University

Language: English

Topic: Bone Metabolism and Diseases

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,420