Bone Morphogenetic Proteins for Nucleus Pulposus Regeneration

Matrix production by nucleus pulposus (NP) cells, the cells residing in the center of the intervertebral disc, can be stimulated by growth factors. Bone morphogenetic proteins (BMPs) hold great promise. Although BMP2 and BMP7 have been used most frequently, other BMPs have also shown potential for NP regeneration. Heterodimers may be more potent than single homodimers, but it is not known whether combinations of homodimers would perform equally well. In this study, we compared BMP2, BMP4, BMP6, and BMP7, their combinations and heterodimers, for regeneration by human NP cells. The BMPs investigated induced variable matrix deposition by NP cells. BMP4 was the most potent, both in the final neotissue glysosaminoglycan content and incorporation efficiency. Heterodimers BMP2/6H and BMP2/7H were more potent than their respective homodimer combinations, but not the BMP4/7H heterodimer. The current results indicate that BMP4 might have a high potential for regeneration of the intervertebral disc. Moreover, the added value of BMP heterodimers over their respective homodimer BMP combinations depends on the BMP combination applied.

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Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice

Cell Death and Disease ◽

10.1038/s41419-019-1985-3 ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 1

Author(s):

Changli Zhang ◽

Madeline P. Smith ◽

George K. Zhou ◽

Alon Lai ◽

Robert C. Hoy ◽

...

Keyword(s):

Intervertebral Disc ◽

Nucleus Pulposus ◽

Cell Loss ◽

Akt Signaling ◽

Protective Effects ◽

Needle Puncture ◽

Matrix Degradation ◽

Ph Domain ◽

Matrix Deposition ◽

Matrix Production

Abstract Back pain is a leading cause of global disability and is strongly associated with intervertebral disc (IVD) degeneration (IDD). Hallmarks of IDD include progressive cell loss and matrix degradation. The Akt signaling pathway regulates cellularity and matrix production in IVDs and its inactivation is known to contribute to a catabolic shift and increased cell loss via apoptosis. The PH domain leucine-rich repeat protein phosphatase (Phlpp1) directly regulates Akt signaling and therefore may play a role in regulating IDD, yet this has not been investigated. The aim of this study was to investigate if Phlpp1 has a role in Akt dysregulation during IDD. In human IVDs, Phlpp1 expression was positively correlated with IDD and the apoptosis marker cleaved Caspase-3, suggesting a key role of Phlpp1 in the progression of IDD. In mice, 3 days after IVD needle puncture injury, Phlpp1 knockout (KO) promoted Akt phosphorylation and cell proliferation, with less apoptosis. At 2 and 8 months after injury, Phlpp1 deficiency also had protective effects on IVD cellularity, matrix production, and collagen structure as measured with histological and immunohistochemical analyses. Specifically, Phlpp1-deletion resulted in enhanced nucleus pulposus matrix production and more chondrocytic cells at 2 months, and increased IVD height, nucleus pulposus cellularity, and extracellular matrix deposition 8 months after injury. In conclusion, Phlpp1 has a role in limiting cell survival and matrix degradation in IDD and research targeting its suppression could identify a potential therapeutic target for IDD.

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Tissue Engineering of the Intervertebral Disc With Cultured Nucleus Pulposus Cells Using Atelocollagen Scaffold and Growth Factors

Spine ◽

10.1097/brs.0b013e31823c8603 ◽

2012 ◽

Vol 37 (6) ◽

pp. 452-458 ◽

Cited By ~ 35

Author(s):

Kwang-Il Lee ◽

Seong-Hwan Moon ◽

Hyang Kim ◽

Un-Hye Kwon ◽

Ho-Joong Kim ◽

...

Keyword(s):

Tissue Engineering ◽

Growth Factors ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Nucleus Pulposus Cells

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LIM mineralization protein-1 suppresses TNF-α induced intervertebral disc degeneration by maintaining nucleus pulposus extracellular matrix production and inhibiting matrix metalloproteinases expression

Journal of Orthopaedic Research® ◽

10.1002/jor.22732 ◽

2014 ◽

Vol 33 (3) ◽

pp. 294-303 ◽

Cited By ~ 28

Author(s):

Hui Liu ◽

Hehai Pan ◽

Hao Yang ◽

Jianru Wang ◽

Kuibo Zhang ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Metalloproteinases ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Tnf Α ◽

Extracellular Matrix Production ◽

Matrix Production

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Faculty Opinions recommendation of Age-related changes in the extracellular matrix of nucleus pulposus and anulus fibrosus of human intervertebral disc.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1159890.621321 ◽

2009 ◽

Author(s):

Honorio Benzon ◽

Khalid Malik

Keyword(s):

Extracellular Matrix ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Anulus Fibrosus ◽

Age Related ◽

Age Related Changes

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Injectable Nucleus Pulposus Derived-ECM Hydrogel Functionalised with Chondroitin Sulfate for Intervertebral Disc Regeneration

SSRN Electronic Journal ◽

10.2139/ssrn.3610436 ◽

2020 ◽

Author(s):

Chiara Borrell ◽

Conor T. Buckley

Keyword(s):

Intervertebral Disc ◽

Chondroitin Sulfate ◽

Nucleus Pulposus ◽

Disc Regeneration ◽

Intervertebral Disc Regeneration

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Towards Tissue-Specific Stem Cell Therapy for the Intervertebral Disc: PPARδ Agonist Increases the Yield of Human Nucleus Pulposus Progenitor Cells in Expansion

Surgeries ◽

10.3390/surgeries2010008 ◽

2021 ◽

Vol 2 (1) ◽

pp. 92-104

Author(s):

Xingshuo Zhang ◽

Julien Guerrero ◽

Andreas S. Croft ◽

Katharina A.C. Oswald ◽

Christoph E. Albers ◽

...

Keyword(s):

Intervertebral Disc ◽

Progenitor Cells ◽

Nucleus Pulposus ◽

Nucleus Pulposus Cell ◽

Treated Group ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Hematopoietic Stem ◽

Heterogeneous Nucleus ◽

Red Dye

(1) Background: Low back pain (LBP) is often associated with intervertebral disc degeneration (IVDD). Autochthonous progenitor cells isolated from the center, i.e., the nucleus pulposus, of the IVD (so-called nucleus pulposus progenitor cells (NPPCs)) could be a future cell source for therapy. The NPPCs were also identified to be positive for the angiopoietin-1 receptor (Tie2). Similar to hematopoietic stem cells, Tie2 might be involved in peroxisome proliferator-activated receptor delta (PPARδ) agonist-induced self-renewal regulation. The purpose of this study was to investigate whether a PPARδ agonist (GW501516) increases the Tie2+ NPPCs’ yield within the heterogeneous nucleus pulposus cell (NPC) population. (2) Methods: Primary NPCs were treated with 10 µM of GW501516 for eight days. Mitochondrial mass was determined by microscopy, using mitotracker red dye, and the relative gene expression was quantified by qPCR, using extracellular matrix and mitophagy-related genes. (3) The NPC’s group treated with the PPARδ agonist showed a significant increase of the Tie2+ NPCs yield from ~7% in passage 1 to ~50% in passage two, compared to the NPCs vehicle-treated group. Furthermore, no significant differences were found among treatment and control, using qPCR and mitotracker deep red. (4) Conclusion: PPARδ agonist could help to increase the Tie2+ NPCs yield during NPC expansion.

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Expression of miR-195 and its target gene Bcl-2 in human intervertebral disc degeneration and their effects on nucleus pulposus cell apoptosis

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-021-02538-8 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Xue-Lin Lin ◽

Zhao-Yun Zheng ◽

Qing-Shan Zhang ◽

Zhen Zhang ◽

You-Zhi An

Keyword(s):

Cell Proliferation ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Rat Model ◽

Cell Apoptosis ◽

Intervertebral Disc Degeneration ◽

Target Gene ◽

Blank Group ◽

Tnf Α

Abstract Objective To investigate the expression of miR-195 and its target gene Bcl-2 in intervertebral disc degeneration (IVDD) and its effect on nucleus pulposus (NP) cell apoptosis. Methods The expressions of miR-195 and Bcl-2 in NP tissues of IVDD patients were quantified by qRT-PCR and western blotting, respectively. NP cells were divided into blank group, TNF-α group, TNF-α + miR-NC group, TNF-α + siBcl-2 group, and TNF-α + miR-195 inhibitors + siBcl-2 group. Cell proliferation was detected by MTT assay, cell apoptosis evaluated by flow cytometry, and mitochondrial membrane potential (MMP) tested by JC-1 staining. Moreover, the function of miR-195 on IVDD in vivo was investigated using a puncture-induced IVDD rat model. Results IVDD patients had significantly increased miR-195 expression and decreased Bcl-2 protein expression in NP tissues. The expression of miR-195 was negatively correlated with the expression of Bcl-2 in IVDD patients. Dual-luciferase reporter gene assay indicated that Bcl-2 was a target gene of miR-195. In comparison with blank group, TNF-α group showed decreased cell proliferation and MMP, increased cell apoptosis, upregulated expression of miR-195, Bax, and cleaved caspase 3, and downregulated Bcl-2 protein, while these changes were attenuated by miR-195 inhibitors. Additionally, siBcl-2 can reverse the protective effect of miR-195 inhibitors on TNF-α-induced NP cells. Besides, inhibition of miR-195 alleviated IVDD degeneration and NP cell apoptosis in the rat model. Conclusion MiR-195 was significantly upregulated in NP tissues of IVDD patients, and inhibition of miR-195 could protect human NP cells from TNF-α-induced apoptosis via upregulation of Bcl-2.

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Effects of bone morphogenetic proteins on epithelial repair

Experimental Biology and Medicine ◽

10.1177/15353702211028193 ◽

2021 ◽

pp. 153537022110281

Author(s):

Yu Hou ◽

Yu-Xi He ◽

Jia-Hao Zhang ◽

Shu-Rong Wang ◽

Yan Zhang

Keyword(s):

Growth Factors ◽

Epithelial Cells ◽

Bone Morphogenetic Proteins ◽

Epithelial Tissue ◽

Epithelial Repair ◽

Multiple Functions ◽

Epithelial Damage ◽

Damage Repair ◽

And Migration ◽

Proliferation And Migration

Epithelial tissue has important functions such as protection, secretion, and sensation. Epithelial damage is involved in various pathological processes. Bone morphogenetic proteins (BMPs) are a class of growth factors with multiple functions. They play important roles in epithelial cells, including in differentiation, proliferation, and migration during the repair of the epithelium. This article reviews the functions and mechanisms of the most profoundly studied BMPs in the process of epithelial damage repair and their clinical significance.

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Bone marrow niche crosses paths with BMPs: a road to protection and persistence in CML

Biochemical Society Transactions ◽

10.1042/bst20190221 ◽

2019 ◽

Vol 47 (5) ◽

pp. 1307-1325 ◽

Cited By ~ 1

Author(s):

Caroline Busch ◽

Helen Wheadon

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Bone Morphogenetic Proteins ◽

Kinase Inhibitor ◽

Survival Rates ◽

High Survival ◽

Bone Marrow Niche ◽

Matrix Deposition ◽

Bmp Receptors ◽

Number Of Patients

Abstract Chronic myeloid leukaemia (CML) is a paradigm of precision medicine, being one of the first cancers to be treated with targeted therapy. This has revolutionised CML therapy and patient outcome, with high survival rates. However, this now means an ever-increasing number of patients are living with the disease on life-long tyrosine kinase inhibitor (TKI) therapy, with most patients anticipated to have near normal life expectancy. Unfortunately, in a significant number of patients, TKIs are not curative. This low-level disease persistence suggests that despite a molecularly targeted therapeutic approach, there are BCR-ABL1-independent mechanisms exploited to sustain the survival of a small cell population of leukaemic stem cells (LSCs). In CML, LSCs display many features akin to haemopoietic stem cells, namely quiescence, self-renewal and the ability to produce mature progeny, this all occurs through intrinsic and extrinsic signals within the specialised microenvironment of the bone marrow (BM) niche. One important avenue of investigation in CML is how the disease highjacks the BM, thereby remodelling this microenvironment to create a niche, which enables LSC persistence and resistance to TKI treatment. In this review, we explore how changes in growth factor levels, in particular, the bone morphogenetic proteins (BMPs) and pro-inflammatory cytokines, impact on cell behaviour, extracellular matrix deposition and bone remodelling in CML. We also discuss the challenges in targeting LSCs and the potential of dual targeting using combination therapies against BMP receptors and BCR-ABL1.

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