Senolytics ameliorate the failure of bone regeneration through the cell senescence-related inflammatory signalling pathway

Xinchen Wang; Yue Zhou; Chuyi Luo; Jianxin Zhao; Yuna Ji; Zheng Wang; Pengchao Zheng; Dingji Li; Yuhan Shi; Aki Nishiura; Naoyuki Matsumoto; Yoshitomo Honda; Baoshan Xu; Fang Huang

doi:10.1016/j.biopha.2024.116606

Senolytics ameliorate the failure of bone regeneration through the cell senescence-related inflammatory signalling pathway

Biomed Pharmacother. 2024 Apr 25:175:116606. doi: 10.1016/j.biopha.2024.116606. Online ahead of print.

Authors

Xinchen Wang¹, Yue Zhou², Chuyi Luo³, Jianxin Zhao³, Yuna Ji⁴, Zheng Wang⁴, Pengchao Zheng⁴, Dingji Li⁴, Yuhan Shi⁴, Aki Nishiura³, Naoyuki Matsumoto³, Yoshitomo Honda⁵, Baoshan Xu⁶, Fang Huang⁷

Affiliations

¹ Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Orthodontics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan.
² Department of Orthodontics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan; Department of Stomatological Research Center, Affiliated Hospital of Yunnan University, Kunming, Yunnan, China.
³ Department of Orthodontics, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan.
⁴ Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong, China.
⁵ Department of Oral Anatomy, Osaka Dental University, 8-1 Kuzuhahanazonocho, Hirakata, Osaka 573-1121, Japan. Electronic address: honda-y@cc.osaka-dent.ac.jp.
⁶ Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: xubsh3@mail.sysu.edu.cn.
⁷ Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Institute of Stomatological Research, Sun Yat-sen University, Guangzhou, Guangdong, China. Electronic address: hfang@mail.sysu.edu.cn.

PMID: 38670048
DOI: 10.1016/j.biopha.2024.116606

Abstract

Stress-induced premature senescent (SIPS) cells induced by various stresses deteriorate cell functions. Dasatinib and quercetin senolytics (DQ) can alleviate several diseases by eliminating senescent cells. α-tricalcium phosphate (α-TCP) is a widely used therapeutic approach for bone restoration but induces bone formation for a comparatively long time. Furthermore, bone infection exacerbates the detrimental prognosis of bone formation during material implant surgery due to oral cavity bacteria and unintentional contamination. It is essential to mitigate the inhibitory effects on bone formation during surgical procedures. Little is known that DQ improves bone formation in Lipopolysaccharide (LPS)-contaminated implants and its intrinsic mechanisms in the study of maxillofacial bone defects. This study aims to investigate whether the administration of DQ ameliorates the impairments on bone repair inflammation and contamination by eliminating SIPS cells. α-TCP and LPS-contaminated α-TCP were implanted into Sprague-Dawley rat calvaria bone defects. Simultaneously, bone formation in the bone defects was investigated with or without the oral administration of DQ. Micro-computed tomography and hematoxylin-eosin staining showed that senolytics significantly enhanced bone formation at the defect site. Histology and immunofluorescence staining revealed that the levels of p21- and p16-positive senescent cells, inflammation, macrophages, reactive oxygen species, and tartrate-resistant acid phosphatase-positive cells declined after administering DQ. DQ could partially alleviate the production of senescent markers and senescence-associated secretory phenotypes in vitro. This study indicates that LPS-contaminated α-TCP-based biomaterials can induce cellular senescence and hamper bone regeneration. Senolytics have significant therapeutic potential in reducing the adverse osteogenic effects of biomaterial-related infections and improving bone formation capacity.

Keywords: Biomaterial; Bone formation; Bone infection; Dasatinib and quercetin; Senescence; Senolytics.