N-Cadherin-Mediated Signaling Regulates Cell Phenotype for Nucleus Pulposus Cells of the Intervertebral Disc

Hwang, Priscilla Y.; Jing, Liufang; Michael, Keith W.; Richardson, William J.; Chen, Jun; Setton, Lori A.

doi:10.1007/s12195-014-0373-4

Cited by 33 publications

(56 citation statements)

References 49 publications

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“…This confirms the findings of previous studies that reported that mechanical overloading promoted matrix catabolism [11]. Previous studies have also indicated that N-CDH-mediated signaling promoted NP cell matrix production, whereas the blockage of N-CDH-mediated signaling resulted in the loss of NP cell matrix production [17, 18]. In line with this, we found that N-CDH overexpression partly promoted NP matrix biosynthesis under high-magnitude (20% deformation) compression, indicating that N-CDH plays an important role in resisting high-magnitude compression-induced NP matrix catabolism.…”

Section: Discussionsupporting

confidence: 90%

“…Several studies have identified N-CDH expression in NP cells at either the transcriptional or protein level, regardless of animal species [15-18]. It is also worth mentioning that N-CDH expression decreases with disc aging and disc degeneration and that the decrease in N-CDH expression coincides with those degenerative disc changes [15, 16].…”

Section: Discussionmentioning

confidence: 99%

“…It is also worth mentioning that N-CDH expression decreases with disc aging and disc degeneration and that the decrease in N-CDH expression coincides with those degenerative disc changes [15, 16]. Hence, several research teams have proposed and verified that N-CDH-mediated signaling is necessary for maintaining normal NP biology [17, 18]. In this study, high-magnitude (20% deformation) compression significantly down-regulated N-CDH expression compared with low-magnitude (2% deformation) compression.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, several studies have demonstrated that N-CDH is a specific molecule that is highly expressed in normal disc NP cells compared with degenerative NP cells, adjacent disc annulus fibrosus cells and cartilage endplate cells [15, 16]. In addition, N-CDH-mediated signaling helps to maintain the normal juvenile NP phenotype and NP matrix synthesis in vitro [17, 18]. Finally, N-CDH can regulate cell behaviors, cell phenotypes and other pathological phenomena in other tissues [13, 14].…”

Section: Introductionmentioning

confidence: 99%

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N-Cadherin Maintains the Healthy Biology of Nucleus Pulposus Cells under High-Magnitude Compression

Wang

Leng²,

Zhao³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Mechanical load can regulate disc nucleus pulposus (NP) biology in terms of cell viability, matrix homeostasis and cell phenotype. N-cadherin (N-CDH) is a molecular marker of NP cells. This study investigated the role of N-CDH in maintaining NP cell phenotype, NP matrix synthesis and NP cell viability under high-magnitude compression. Methods: Rat NP cells seeded on scaffolds were perfusion-cultured using a self-developed perfusion bioreactor for 5 days. NP cell biology in terms of cell apoptosis, matrix biosynthesis and cell phenotype was studied after the cells were subjected to different compressive magnitudes (low- and high-magnitudes: 2% and 20% compressive deformation, respectively). Non-loaded NP cells were used as controls. Lentivirus-mediated N-CDH overexpression was used to further investigate the role of N-CDH under high-magnitude compression. Results: The 20% deformation compression condition significantly decreased N-CDH expression compared with the 2% deformation compression and control conditions. Meanwhile, 20% deformation compression increased the number of apoptotic NP cells, up-regulated the expression of Bax and cleaved-caspase-3 and down-regulated the expression of Bcl-2, matrix macromolecules (aggrecan and collagen II) and NP cell markers (glypican-3, CAXII and keratin-19) compared with 2% deformation compression. Additionally, N-CDH overexpression attenuated the effects of 20% deformation compression on NP cell biology in relation to the designated parameters. Conclusion: N-CDH helps to restore the cell viability, matrix biosynthesis and cellular phenotype of NP cells under high-magnitude compression.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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N-Cadherin Maintains the Healthy Biology of Nucleus Pulposus Cells under High-Magnitude Compression

Wang

Leng²,

Zhao³

et al. 2017

Cell Physiol Biochem

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“…N-CDH-mediated signaling is helpful to maintain a normal NP cell phenotype and NP matrix synthesis in vitro [29, 30]. In this study, N-CDH up-regulation coincided with better maintenance of the NP cell phenotype and NP matrix synthesis in the dynamic compression group.…”

Section: Discussionmentioning

confidence: 53%

Dynamic Compression Promotes the Matrix Synthesis of Nucleus Pulposus Cells Through Up-Regulating N-CDH Expression in a Perfusion Bioreactor Culture

Yao

et al. 2018

Cell Physiol Biochem

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Background/Aims: An adequate matrix production of nucleus pulposus (NP) cells is an important tissue engineering-based strategy to regenerate degenerative discs. Here, we mainly aimed to investigate the effects and mechanism of mechanical compression (i.e., static compression vs. dynamic compression) on the matrix synthesis of three-dimensional (3D) cultured NP cells in vitro. Methods: Rat NP cells seeded on small intestinal submucosa (SIS) cryogel scaffolds were cultured in the chambers of a self-developed, mechanically active bioreactor for 10 days. Meanwhile, the NP cells were subjected to compression (static compression or dynamic compression at a 10% scaffold deformation) for 6 hours once per day. Unloaded NP cells were used as controls. The cellular phenotype and matrix biosynthesis of NP cells were investigated by real-time PCR and Western blotting assays. Lentivirus-mediated N-cadherin (N-CDH) knockdown and an inhibitor, LY294002, were used to further investigate the role of N-CDH and the PI3K/Akt pathway in this process. Results: Dynamic compression better maintained the expression of cell-specific markers (keratin-19, FOXF1 and PAX1) and matrix macromolecules (aggrecan and collagen II), as well as N-CDH expression and the activity of the PI3K/Akt pathway, in the 3D-cultured NP cells compared with those expression levels and activity in the cells grown under static compression. Further analysis showed that the N-CDH knockdown significantly down-regulated the expression of NP cell-specific markers and matrix macromolecules and inhibited the activation of the PI3K/Akt pathway under dynamic compression. However, inhibition of the PI3K/Akt pathway had no effects on N-CDH expression but down-regulated the expression of NP cell-specific markers and matrix macromolecules under dynamic compression. Conclusion: Dynamic compression increases the matrix synthesis of 3D-cultured NP cells compared with that of the cells under static compression, and the N-CDH-PI3K/Akt pathway is involved in this regulatory process. This study provides a promising strategy to promote the matrix deposition of tissue-engineered NP tissue in vitro prior to clinical transplantation.

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Hyperosmolarity induces notochordal cell differentiation with aquaporin3 upregulation and reduced N‐cadherin expression

Palacio-Mancheno

Evashwick‐Rogler

Laudier

et al. 2017

Journal Orthopaedic Research

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The nucleus pulposus (NP) of intervertebral discs (IVD) undergoes dramatic changes with aging including loss of its gelatinous structure and large, vacuolated notochordal cells (NCs) in favor of a matrix-rich structure populated by small NP cells (sNPCs). NP maturation also involves a loading-pattern shift from pressurization to matrix deformations, and these events are thought to predispose to degeneration. Little is known of the triggering events and cellular alterations involved with NP maturation, which remains a fundamental open spinal mechanobiology question. A mouse IVD organ culture model was used to test the hypotheses that hyperosmotic overloading will induce NP maturation with transition of NCs to sNPCs while also increasing matrix accumulation and altering osmoregulatory and mechanotransductive proteins. Results indicated that static hyperosmolarity, as might occur during growth, caused maturation of NCs to sNPCs and involved a cellular differentiation process since known NC markers (cytokeratin-8, -19, and sonic hedgehog) persisted without increased cell apoptosis. Osmosensitive channels Aquaporin 3 (Aqp3) and transient receptor potential vanilloid-4 (TRPV4) expression were both modified with altered osmolarity, but increased Aqp3 with hyperosmolarity was associated with NC to sNPC differentiation. NC to sNPC differentiation was accompanied by a shift in cellular mechanotransduction proteins with decreased N-cadherin adhesions and increased Connexin 43 connexons. We conclude that hyperosmotic overloading can promote NC differentiation into sNPCs. This study identified osmolarity as a triggering mechanism for notochordal cell differentiation with associated shifts in osmoregulatory and mechanotransductive proteins that are likely to play important roles in intervertebral disc aging. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:788-798, 2018.

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N-Cadherin-Mediated Signaling Regulates Cell Phenotype for Nucleus Pulposus Cells of the Intervertebral Disc

Cited by 33 publications

References 49 publications

N-Cadherin Maintains the Healthy Biology of Nucleus Pulposus Cells under High-Magnitude Compression

N-Cadherin Maintains the Healthy Biology of Nucleus Pulposus Cells under High-Magnitude Compression

Dynamic Compression Promotes the Matrix Synthesis of Nucleus Pulposus Cells Through Up-Regulating N-CDH Expression in a Perfusion Bioreactor Culture

Hyperosmolarity induces notochordal cell differentiation with aquaporin3 upregulation and reduced N‐cadherin expression

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