Inhibition of RhoA/MRTF-A signaling alleviates nucleus pulposus fibrosis induced by mechanical stress overload

Song, Mengxiong; Zhang, Yiran; Sun, Yi; Kong, Meng; Han, Shuo; Wang, Chao; Wang, Yan; Xu, Derong; Tu, Qihao; Zhu, Kai; Sun, Chong; Li, Guanghui; Zhao, Han; Ma, Xuexiao

doi:10.1080/03008207.2021.1952193

Cited by 8 publications

(19 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is limited data that shows the regulation of Scx, Mmp-3, and Mmp-13 by MRTF. However, MRTF has been shown to regulate another Mmp, Mmp-12, in nucleus pulposus cells [72]. Intriguingly, in the present study, we identified a decrease in the nuclear proportion of transcription factor SCX by TR100 treatment.…”

Section: Discussionsupporting

confidence: 69%

Destabilization of F-actin by Mechanical Stress Deprivation or Tpm3.1 Inhibition Promotes a Pathological Phenotype in Tendon Cells

Parreno

Inguito

Schofield

et al. 2022

Preprint

View full text Add to dashboard Cite

The actin cytoskeleton is a central mediator between mechanical force and cellular phenotype. In tendon, it is speculated that mechanical stress deprivation regulates gene expression by filamentous (F-) actin destabilization. However, the molecular mechanisms that stabilize tenocyte F-actin networks remain unclear. Tropomyosins (Tpms) are master regulators of F-actin networks. There are over 40 mammalian Tpm isoforms, with each isoform having the unique capability to stabilize F-actin sub-populations. Thus, the specific Tpm(s) expressed by a cell defines overall F-actin organization. Here, we investigated F-actin destabilization by stress deprivation of tendon and tested the hypothesis that stress fiber-associated Tpm(s) stabilize tenocyte F-actin to regulate cellular phenotype. Stress deprivation of mouse tail tendon fascicles downregulated tenocyte genes (collagen-I, tenascin-C, scleraxis, α-smooth muscle actin) and upregulated matrix metalloproteinase-3. Concomitant with mRNA modulation were increases in DNAse-I/Phallodin (G/F-actin) staining, confirming F-actin destabilization by tendon stress deprivation. To investigate the molecular regulation of F-actin stabilization, we first identified the Tpms expressed by mouse tendons. Tendon cells from different origins (tail, Achilles, plantaris) express three isoforms in common: Tpm1.6, 3.1, and 4.2. We examined the function of Tpm3.1 since we previously determined that it stabilizes F-actin stress fibers in lens epithelial cells. Tpm3.1 associated with F-actin stress fibers in native and primary tendon cells. Inhibition of Tpm3.1 depolymerized F-actin, leading to decreases in tenogenic expression, increases in chondrogenic expression, and enhancement of protease expression. These expression changes by Tpm3.1 inhibition are consistent with tendinosis progression. A further understanding of F-actin stability in musculoskeletal cells could lead to new therapeutic interventions to prevent alterations in cellular phenotype during disease progression.

show abstract

Section: Discussionsupporting

confidence: 69%

Destabilization of F-actin by Mechanical Stress Deprivation or Tpm3.1 Inhibition Promotes a Pathological Phenotype in Tendon Cells

Parreno

Inguito

Schofield

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Collagen II expression in the NP decreases with aging and degeneration [ 21 ]. Various animal model studies suggest that early IDD involves a transient increase in collagen II, changing gelatinous NP into a cartilaginous entity before further remodeling into fibrous tissue [ 25 , 49 ], characterized by an increase in collagen I. Accumulation of collagen I has been evidenced in human IDD [ 6 , 21 , 50 ], animal models of IDD induced by aging [ 6 , 21 , 25 , 49 , 50 , 51 ], overloading [ 52 ] or injury [ 6 , 26 , 36 , 49 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ], as well as NP cells under stress [ 36 , 50 ] or treatment of TGF-β [ 59 , 60 ]. Collagen III and collagen I are primary ECM components produced by myofibroblasts that are proposed to increase tissue stiffness and tensile force [ 61 ] and decrease tissue compressive strength.…”

Section: Matrices In Np Fibrosismentioning

confidence: 99%

“…Interestingly, inflammatory macrophages were shown to be capable of undergoing myofibroblast transition in renal fibrosis [ 75 ]. The finding of colocalization of the macrophage marker MMP-12 with α-SMA in the NP of induced IDD appears to support such a transition [ 6 , 50 ].…”

Section: Cell Composition In Np Fibrosismentioning

confidence: 99%

“…Connective tissue growth factor (CTGF, or CCN2) is the putative downstream element of TGF-β1 and can induce the proliferation of active fibroblasts and contribute to tissue fibrosis [ 93 ]. CTGF was found to be upregulated in overloaded human NP cells [ 50 ] and IVDs [ 94 ]. The role of Sox9 and CTGF in NP fibrosis warrants further exploration.…”

Section: Regulation Of Np Fibrosismentioning

confidence: 99%

“…Cell shape control is crucial to the matrix stiffness-triggered fibroblastic phenotype in NP cells [ 117 ]. Upregulation of collagen I, CTGF and α-SMA was observed in NP cells cultured on stiff matrices (41.7 Kpa) [ 52 ], under cyclic stretching [ 50 ] and in a bipedal model [ 52 ]. Increased collagen I was also observed in AF progenitors under cyclic tensile strain [ 67 ].…”

Section: Regulation Of Np Fibrosismentioning

confidence: 99%

See 2 more Smart Citations

Current Perspectives on Nucleus Pulposus Fibrosis in Disc Degeneration and Repair

Sun

Lyu

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

A growing body of evidence in humans and animal models indicates an association between intervertebral disc degeneration (IDD) and increased fibrotic elements in the nucleus pulposus (NP). These include enhanced matrix turnover along with the abnormal deposition of collagens and other fibrous matrices, the emergence of fibrosis effector cells, such as macrophages and active fibroblasts, and the upregulation of the fibroinflammatory factors TGF-β1 and IL-1/-13. Studies have suggested a role for NP cells in fibroblastic differentiation through the TGF-βR1-Smad2/3 pathway, inflammatory activation and mechanosensing machineries. Moreover, NP fibrosis is linked to abnormal MMP activity, consistent with the role of matrix proteases in regulating tissue fibrosis. MMP-2 and MMP-12 are the two main profibrogenic markers of myofibroblastic NP cells. This review revisits studies in the literature relevant to NP fibrosis in an attempt to stratify its biochemical features and the molecular identity of fibroblastic cells in the context of IDD. Given the role of fibrosis in tissue healing and diseases, the perspective may provide new insights into the pathomechanism of IDD and its management.

show abstract

Overloaded axial stress activates the Wnt/β-Catenin pathway in nucleus pulposus cells of adult degenerative scoliosis combined with intervertebral disc degeneration

Cai¹,

Luo²,

Xi³

et al. 2023

Mol Biol Rep

View full text Add to dashboard Cite

Background Intervertebral disc degeneration (IVDD) is the initiating factor of adult degenerative scoliosis (ADS), and ADS further accelerates IVDD, creating a vicious cycle. Nevertheless, the role of the Wnt/β-Catenin pathway in ADS combined with IVDD (ADS-IVDD) remains a mystery. Accordingly, this study was proposed to investigate the effect of axial stress on the Wnt/β-Catenin pathway in nucleus pulposus cells (NPCs) isolated from DS-IVDD patients. Methods Normal NPCs (N-NPC) were purchased and the NPCs of young (25–30 years; Y-NPC) and old (65–70 years; O-NPC) from ADS-IVDD patients were primary cultured. After treatment of NPC with overloaded axial pressure, CCK-8 and Annexin V-FITC kits were applied for detecting proliferation and apoptosis of N-NPC, Y-NPC and O-NPC, and western blotting was performed to assess the expression of Wnt 3a, β-Catenin, NPC markers and apoptosis markers (Bax, Bcl2 and Caspase 3). Results N-NPC, Y-NPC and O-NPC were mainly oval, polygonal and spindle-shaped with pseudopods, and the cell morphology tended to be flattened with age. N-NPC, Y-NPC and O-NPC were capable of synthesizing proteoglycans and expressing the NPC markers (Collagen II and Aggrecan). Notably, the expression of Wnt 3a, β-Catenin, Collagen II and Aggrecan was reduced in N-NPC, Y-NPC and O-NPC in that order. After overload axial stress treatment, cell viability of N-NPC and Y-NPC was significantly reduced, and the percentage of apoptosis and expression of Wnt 3a and β-Catenin were significantly increased. Conclusions Overloaded axial pressure activates the Wnt/β-Catenin pathway to suppress proliferation and facilitate apoptosis of NPC in ADS-IVDD patients.

show abstract

Inhibition of RhoA/MRTF-A signaling alleviates nucleus pulposus fibrosis induced by mechanical stress overload

Cited by 8 publications

References 76 publications

Destabilization of F-actin by Mechanical Stress Deprivation or Tpm3.1 Inhibition Promotes a Pathological Phenotype in Tendon Cells

Destabilization of F-actin by Mechanical Stress Deprivation or Tpm3.1 Inhibition Promotes a Pathological Phenotype in Tendon Cells

Current Perspectives on Nucleus Pulposus Fibrosis in Disc Degeneration and Repair

Overloaded axial stress activates the Wnt/β-Catenin pathway in nucleus pulposus cells of adult degenerative scoliosis combined with intervertebral disc degeneration

Contact Info

Product

Resources

About