Biophysical Modulation of the Mitochondrial Metabolism and Redox in Bone Homeostasis and Osteoporosis: How Biophysics Converts into Bioenergetics

Abstract

Bone-forming cells build mineralized microstructure and couple with bone-resorbing cells, harmonizing bone mineral acquisition, and remodeling to maintain bone mass homeostasis. Mitochondrial glycolysis and oxidative phosphorylation pathways together with ROS generation meet the energy requirement for bone-forming cell growth and differentiation, respectively. Moderate mechanical stimulations, such as weight loading, physical activity, ultrasound, vibration, and electromagnetic field stimulation, etc., are advantageous to bone-forming cell activity, promoting bone anabolism to compromise osteoporosis development. A plethora of molecules, including ion channels, integrins, focal adhesion kinases, and myokines, are mechanosensitive and transduce mechanical stimuli into intercellular signaling, regulating growth, mineralized extracellular matrix biosynthesis, and resorption. Mechanical stimulation changes mitochondrial respiration, biogenesis, dynamics, calcium influx, and redox, whereas mechanical disuse induces mitochondrial dysfunction and oxidative stress, which aggravates bone-forming cell apoptosis, senescence, and dysfunction. The control of the mitochondrial biogenesis activator PGC-1α by NAD+-dependent deacetylase sirtuins or myokine FNDC/irisin or repression of oxidative stress by mitochondrial antioxidant Nrf2 modulates the biophysical stimulation for the promotion of bone integrity. This review sheds light onto the roles of mechanosensitive signaling, mitochondrial dynamics, and antioxidants in mediating the anabolic effects of biophysical stimulation to bone tissue and highlights the remedial potential of mitochondrial biogenesis regulators for osteoporosis.

In Sickness and in Health: The Oxygen Reactive Species and the Bone

“…PGC-1α stimulates Sirtuin 3 activity on osteogenic differentiation ( Buccoliero et al, 2021 ). How different biophysical stimuli may affect mitochondrial metabolism bone was recently reviewed by ( Wang F.-S. et al, 2021 ). In rat skeletal muscle tissue, the expression of PGC-1α and HIF-1α were differently affected by the training regimen (continuous, moderate exercise vs high-intensity interval) ( Ahmadi et al, 2021 ).…”

Synergistic effects of epigallocatechin gallate and l-theanine in nerve repair and regeneration by anti-amyloid damage, promoting metabolism, and nourishing nerve cells

“…DEGs in the Aβ 25−35 /EGCG group were mainly enriched in cell translation, extracellular matrix, wound healing, cytoplasm, and growth factor stimulation (Figure 7B Analysis of the synergistic mechanism of EGCG and L-theanine from the transcriptome level. (1)(2)(3)(4) The results showed that the cluster map of DEGs in the Aβ25-35-vs-Aβ25-35/EGCG + L-theanine was mainly divided into four blocks, of which ( 1) and (3) blocks gene expression trend was opposite to that of other treatment groups, and ( 2) and ( 4) blocks gene expression trend were very similar to that of Aβ 25−35 -vs-Aβ 25−35 /EGCG. The expression level of each gene was calculated using the transcripts per kilobase of exon model per million mapped reads (TPM) after normalizing the expression level of each gene.…”

“…Proteotoxic stress, mitochondrial dysfunction, and genomic instability lead to cellular hyperactivity and are closely associated with age-related degenerative diseases such as atherosclerosis, type 2 diabetes, osteoporosis, and Alzheimer's disease (1)(2)(3). Under various stressful conditions, cells promote mTOR or other growth factors sensitive growth-stimulating pathways, causing cells to exhibit hyperactivity.…”

Effects of Mechanical Stress Stimulation on Function and Expression Mechanism of Osteoblasts

“…Human MSCs (hMSCs) can be gradually remodeled through cell recombination and arrangement and the regulation of smooth muscle cells by the cytoskeleton ( Parandakh et al, 2017 ). Microtubule actin cross-linking factor 1 (MACF1) is a regulator of cytoskeletal dynamics that is necessary for maintaining bone tissue integrity ( Wang et al, 2021a ), whereas actin in the cytoskeleton is mainly involved in mechanical stress ( Zhou et al, 2018 ). The link between mechanical stimulation, integrin/cytoskeleton/Scr/extracellular signal-regulated protein kinase (ERK) signaling pathway activation, and osteocyte survival provides a mechanical basis for the role of mechanical forces in the bone ( Plotkin et al, 2005 ).…”