Mechanical stress determines the configuration of TGFβ activation in articular cartilage

Zhen, Gehua; Guo, Qiaoyue; Li, Yusheng; Wu, Chuanlong; Zhu, Shouan; Wang, Ruomei; Guo, X. Edward; Kim, Byoung Choul; Huang, Jessie; Hu, Yizhong; Yang, Dan; Wan, Mei; Ha, Taekjip; An, Steven S.; Cao, Xu

doi:10.1038/s41467-021-21948-0

Cited by 90 publications

(66 citation statements)

References 89 publications

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“…The latter mechanism requires the association of the latent complex with mechanically resistant ECM. Proof of mechanically driven TGF-β activation by contractile forces on the bond between LAP and αV-integrins has recently been demonstrated to occur in mechanically stressed cartilage [75]. Zhen et al demonstrated that mechanical stress leads to a talin-centered cytoskeletal reorganization in chondrocytes, causing a stiffening that transmits to αv integrins in the release of TGF-β [75].…”

Section: Discussionmentioning

confidence: 99%

Intermittent Dynamic Compression Confers Anabolic Effects in Articular Cartilage

et al. 2021

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(1) Background: Mechanical loading is an essential part of the function and maintenance of the joint. Despite the importance of intermittent mechanical loading, this factor is rarely considered in preclinical models of cartilage, limiting their translatability. The aim of this study was to investigate the effects of intermittent dynamic compression on the extracellular matrix during long-term culture of bovine cartilage explants. (2) Methods: Bovine articular cartilage explants were cultured for 21 days and subjected to 20 min of 1 Hz cyclic compressive loading five consecutive days each week. Cartilage remodeling was investigated in the presence of IGF-1 or TGF-β1, as well as a TGF-β receptor 1 (ALK5) kinase inhibitor and assessed with biomarkers for type II collagen formation (PRO-C2) and fibronectin degradation (FBN-C). (3) Results: Compression of cartilage explants increased the release of PRO-C2 and FBN-C to the conditioned media and, furthermore, IGF-1 and compression synergistically increased PRO-C2 release. Inhibition of ALK5 blocked PRO-C2 and FBN-C release in dynamically compressed explants. (4) Conclusions: Dynamic compression of cartilage explants increases both type II collagen formation and fibronectin degradation, and IGF-1 interacts synergistically with compression, increasing the overall impact on cartilage formation. These data show that mechanical loading is important to consider in translational cartilage models.

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Section: Discussionmentioning

confidence: 99%

Intermittent Dynamic Compression Confers Anabolic Effects in Articular Cartilage

et al. 2021

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“…A high level of TGF-β can disrupt cartilage homeostasis and impair the metabolic activity of chondrocytes. Animal studies have shown that knockdown of αV integrin gene in mouse chondrocytes can reverse TGF-β activation and subsequent abnormalities in articular cartilage metabolism (Zhen et al, 2021). Cytokines in ECM are considered to have a variety of effects on cartilage.…”

Section: Cytokine Signals and Integrinsmentioning

confidence: 99%

“…Mechanical stress can trigger TGFβ activation through αV integrin-mediated signaling pathways. A high level of TGF-β activation has been detected in areas with high mechanical load in cartilage (Zhen et al, 2021).…”

Section: Integrins In Healthy and Osteoarthritic Subchondral Bonementioning

confidence: 99%

Mechanistic Insight Into the Roles of Integrins in Osteoarthritis

Jin

Jiang²,

Wang³

et al. 2021

Front. Cell Dev. Biol.

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Osteoarthritis (OA), one of the most common degenerative diseases, is characterized by progressive degeneration of the articular cartilage and subchondral bone, as well as the synovium. Integrins, comprising a family of heterodimeric transmembrane proteins containing α subunit and β subunit, play essential roles in various physiological functions of cells, such as cell attachment, movement, growth, differentiation, and mechanical signal conduction. Previous studies have shown that integrin dysfunction is involved in OA pathogenesis. This review article focuses on the roles of integrins in OA, especially in OA cartilage, subchondral bone and the synovium. A clear understanding of these roles may influence the future development of treatments for OA.

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“…Mechanosensitive molecules play an important role in converting extracellular mechanical stimuli into biological signals. For example, mechanical stress alters cytoskeleton organization and contraction, prompting integrin signaling to activate TGF-β1 in chondrocytes [ 64 ].…”

Section: Mechanosensitive Molecular Mechanism Underly Bone Mass Homeostasismentioning

confidence: 99%

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

Wang

Chen

et al. 2021

Antioxidants

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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.

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Mechanical stress determines the configuration of TGFβ activation in articular cartilage

Cited by 90 publications

References 89 publications

Intermittent Dynamic Compression Confers Anabolic Effects in Articular Cartilage

Intermittent Dynamic Compression Confers Anabolic Effects in Articular Cartilage

Mechanistic Insight Into the Roles of Integrins in Osteoarthritis

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

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