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  2. PGC-1α/LDHA signaling facilitates glycolysis initiation to regulate mechanically induced bone remodeling under inflammatory microenvironment

PGC-1α/LDHA signaling facilitates glycolysis initiation to regulate mechanically induced bone remodeling under inflammatory microenvironment

  • Bone. 2024 May 22:185:117132. doi: 10.1016/j.bone.2024.117132.
Jiani Liu 1 Jixiao Wang 1 Ziyao Wang 1 Huiying Ren 1 Zijie Zhang 1 Yajing Fu 1 Lan Li 1 Zhiyuan Shen 1 Tianyi Li 1 Shuai Tang 1 Fulan Wei 2
Affiliations

Affiliations

  • 1 Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan 250012, Shandong, China.
  • 2 Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan 250012, Shandong, China. Electronic address: weifl@email.sdu.edu.cn.
Abstract

The mechanosensitivity of inflammation can alter cellular mechanotransduction. However, the underlying mechanism remains unclear. This study aims to investigate the metabolic mechanism of inflammation under mechanical force to guide tissue remodeling better. Herein, we found that inflammation hindered bone remodeling under mechanical force, accompanied by a simultaneous enhancement of Oxidative Phosphorylation (OXPHOS) and glycolysis. The control of metabolism direction through GNE-140 and Visomitin revealed that enhanced glycolysis might act as a compensatory mechanism to resist OXPHOS-induced osteoclastogenesis by promoting osteogenesis. The inhibited osteogenesis induced by inflammatory mechanical stimuli was concomitant with a reduced expression of Peroxisome Proliferator-activated Receptor gamma coactivator 1-alpha (PGC-1α). PGC-1α knockdown impeded osteogenesis under mechanical force and facilitated osteoclastogenesis by enhancing OXPHOS. Conversely, PGC-1α overexpression attenuated the impairment of bone remodeling by inflammatory mechanical signals through promoting glycolysis. This process benefited from the PGC-1α regulation on the transcriptional and translational activity of Lactate Dehydrogenase A (LDHA) and the tight control of the extracellular acidic environment. Additionally, the increased binding between PGC-1α and LDHA proteins might contribute to the glycolysis promotion within the inflammatory mechanical environment. Notably, LDHA suppression effectively eliminated the bone repair effect mediated by PGC-1α overexpression within inflammatory mechanical environments. In conclusion, this study demonstrated a novel molecular mechanism illustrating how inflammation orchestrated glucose metabolism through glycolysis and OXPHOS to affect mechanically induced bone remodeling.

Keywords

Bone remodeling; Glucose metabolism; Inflammation; LDHA; Mechanical force; PGC-1α.

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