Connexin43 in Musculoskeletal System: New Targets for Development and Disease Progression

An, Shuai; Zheng, Shengyuan; Cai, Zijun; Chen, Siyu; Wang, Chen; Li, Yusheng; Deng, Zhenhan

doi:10.14336/ad.2022.0421

Cited by 3 publications

(4 citation statements)

References 160 publications

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“…Connexins are widely expressed in human cells, functioning as electrical communicators in excitable cells, such as neurons. In addition, connexins mediate the exchange of small metabolites and second messengers to regulate cell proliferation and differentiation and the maintenance of tissue homeostasis [ 25 , 26 ]. In addition to intercellular channels, the intercellular domains of connexins can also interact with other proteins, including components of the cytoskeleton and cell signaling pathways [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Development of a cell adhesion-based prognostic model for multiple myeloma: Insights into chemotherapy response and potential reversal of adhesion effects

HU,

WANG,

WANG

et al. 2024

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Multiple myeloma (MM) is a hematologic malignancy notorious for its high relapse rate and development of drug resistance, in which cell adhesion-mediated drug resistance plays a critical role. This study integrated four RNA sequencing datasets (CoMMpass, GSE136337, GSE9782, and GSE2658) and focused on analyzing 1706 adhesion-related genes. Rigorous univariate Cox regression analysis identified 18 key prognosis-related genes, including KIF14, TROAP, FLNA, MSN, LGALS1, PECAM1, and ALCAM, which demonstrated the strongest associations with poor overall survival (OS) in MM patients. To comprehensively evaluate the impact of cell adhesion on MM prognosis, an adhesion-related risk score (ARRS) model was constructed using Lasso Cox regression analysis. The ARRS model emerged as an independent prognostic factor for predicting OS. Furthermore, our findings revealed that a heightened cell adhesion effect correlated with tumor resistance to DNA-damaging drugs, protein kinase inhibitors, and drugs targeting the PI3K/Akt/mTOR signaling pathway. Nevertheless, we identified promising drug candidates, such as tirofiban, pirenzepine, erlotinib, and bosutinib, which exhibit potential in reversing this resistance. In vitro , experiments employing NCIH929, RPMI8226, and AMO1 cell lines confirmed that MM cell lines with high ARRS exhibited poor sensitivity to the aforementioned candidate drugs. By employing siRNA-mediated knockdown of the key ARRS model gene KIF14, we observed suppressed proliferation of NCIH929 cells, along with decreased adhesion to BMSCs and fibronectin. This study presents compelling evidence establishing cell adhesion as a significant prognostic factor in MM. Additionally, potential molecular mechanisms underlying adhesion-related resistance are proposed, along with viable strategies to overcome such resistance. These findings provide a solid scientific foundation for facilitating clinically stratified treatment of MM.

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Section: Resultsmentioning

confidence: 99%

Development of a cell adhesion-based prognostic model for multiple myeloma: Insights into chemotherapy response and potential reversal of adhesion effects

HU,

WANG,

WANG

et al. 2024

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“…Association with Cx43 in musculoskeletal system Cx43 is the most highly expressed Cx isoform in the musculoskeletal system and is considered one of the most important Cxs. It is found in various bone cells, synovial tissue, cartilage, and other tissues, and plays a pivotal role in the musculoskeletal system 140 (Table 1). Panx proteins are also highly expressed during musculoskeletal system development and are considered major GJ proteins.…”

Section: Perspective Of Panxs In Musculoskeletal Systemmentioning

confidence: 99%

Pannexins in the musculoskeletal system: new targets for development and disease progression

Luo,

Zheng,

Xiao

et al. 2024

Bone Res

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During cell differentiation, growth, and development, cells can respond to extracellular stimuli through communication channels. Pannexin (Panx) family and connexin (Cx) family are two important types of channel-forming proteins. Panx family contains three members (Panx1-3) and is expressed widely in bone, cartilage and muscle. Although there is no sequence homology between Panx family and Cx family, they exhibit similar configurations and functions. Similar to Cxs, the key roles of Panxs in the maintenance of physiological functions of the musculoskeletal system and disease progression were gradually revealed later. Here, we seek to elucidate the structure of Panxs and their roles in regulating processes such as osteogenesis, chondrogenesis, and muscle growth. We also focus on the comparison between Cx and Panx. As a new key target, Panxs expression imbalance and dysfunction in muscle and the therapeutic potentials of Panxs in joint diseases are also discussed.

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“…In addition to the above-mentioned mechanosensors, MSCs communicate with neighbouring cells via gap junctions (GJs) formed by connexins 244 , 245 . Six identical or different connexins constitute connexons, which exists in pairs to form GJs between adjacent cells as material exchange channels 245 . Among various kinds of connexins, Cx43 is the most highly expressed subtype 246 .…”

Section: Mechanisms Involved In Biomaterials-induced Osteogenic Diffe...mentioning

confidence: 99%

“…Among various kinds of connexins, Cx43 is the most highly expressed subtype 246 . As a communication hub, it functions through special C-termini, helping cells to sense and respond to mechanical stimuli from ECM 245 .…”

Section: Mechanisms Involved In Biomaterials-induced Osteogenic Diffe...mentioning

confidence: 99%

Integrating physicomechanical and biological strategies for BTE: biomaterials-induced osteogenic differentiation of MSCs

Shi¹,

Zhou²,

Wang³

et al. 2023

Theranostics

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Large bone defects are a major global health concern. Bone tissue engineering (BTE) is the most promising alternative to avoid the drawbacks of autograft and allograft bone. Nevertheless, how to precisely control stem cell osteogenic differentiation has been a long-standing puzzle. Compared with biochemical cues, physicomechanical stimuli have been widely studied for their biosafety and stability. The mechanical properties of various biomaterials (polymers, bioceramics, metal and alloys) become the main source of physicomechanical stimuli. By altering the stiffness, viscoelasticity, and topography of materials, mechanical stimuli with different strengths transmit into precise signals that mediate osteogenic differentiation. In addition, externally mechanical forces also play a critical role in promoting osteogenesis, such as compression stress, tensile stress, fluid shear stress and vibration, etc. When exposed to mechanical forces, mesenchymal stem cells (MSCs) differentiate into osteogenic lineages by sensing mechanical stimuli through mechanical sensors, including integrin and focal adhesions (FAs), cytoskeleton, primary cilium, ions channels, gap junction, and activating osteogenic-related mechanotransduction pathways, such as yes associated proteins (YAP)/TAZ, MAPK, Rho-GTPases, Wnt/β-catenin, TGFβ superfamily, Notch signaling. This review summarizes various biomaterials that transmit mechanical signals, physicomechanical stimuli that directly regulate MSCs differentiation, and the mechanical transduction mechanisms of MSCs. This review provides a deep and broad understanding of mechanical transduction mechanisms and discusses the challenges that remained in clinical translocation as well as the outlook for the future improvements.

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Connexin43 in Musculoskeletal System: New Targets for Development and Disease Progression

Cited by 3 publications

References 160 publications

Development of a cell adhesion-based prognostic model for multiple myeloma: Insights into chemotherapy response and potential reversal of adhesion effects

Development of a cell adhesion-based prognostic model for multiple myeloma: Insights into chemotherapy response and potential reversal of adhesion effects

Pannexins in the musculoskeletal system: new targets for development and disease progression

Integrating physicomechanical and biological strategies for BTE: biomaterials-induced osteogenic differentiation of MSCs

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