Link Protein N-terminal Peptide Binds to Bone Morphogenetic Protein (BMP) Type II Receptor and Drives Matrix Protein Expression in Rabbit Intervertebral Disc Cells

Wang, Zili; Weitzmann, M. Neale; Sangadala, Sreedhara; Hutton, William; Yoon, S. Tim

doi:10.1074/jbc.m113.451948

Cited by 39 publications

(52 citation statements)

References 40 publications

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“…20,[29][30][31] It is however, not known whether Link N or MSCs alone can restore the proteoglycan content in larger discs with early degeneration. It is also not known whether a combination of Link N and MSCs would have an additive effect.…”

Section: Resultsmentioning

confidence: 99%

“…[30][31][32][33][34] Although Link N is cleaved by AF cells, the resulting N-terminal eight amino acid peptide appears to be proteolytically stable and retains biological activity (unpublished data). Studies utilizing isolated IVD cells in vitro showed that Link N could induce collagen and proteoglycan message levels and result in increased incorporation of radioactive 35 SO 4 into newly synthesized proteoglycans.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Link N and Mesenchymal Stem Cells Can Induce Regeneration of the Early Degenerate Intervertebral Disc

Mwale

Wang

Roughley

et al. 2014

Tissue Engineering Part A

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Link N is a naturally occurring peptide that can stimulate proteoglycan synthesis in intervertebral disc (IVD) cells. IVD repair can also potentially be enhanced by mesenchymal stem cell (MSC) supplementation to maximize extracellular matrix (ECM) production. In a previous study, we have shown that Link N can inhibit osteogenesis and increase the chondrogenesis of MSCs in vitro. The aim of the present study was to determine the potential of MSCs and Link N alone or in combination with regard to tissue repair in the degenerate disc. Bovine IVDs with trypsin-induced degeneration were treated with MSCs, Link N, or a combination of MSCs and Link N. Trypsintreated discs were also injected with phosphate-buffered saline to serve as a degeneration control. The ECM proteins and proteoglycans were extracted from the inner nucleus pulposus (NP) of the discs, and sulfated glycosaminoglycans (GAGs) were analyzed by the dimethyl methylene blue dye-binding assay. The expression of type II collagen was analyzed by western blot. To track the MSCs after injection, MSCs were labeled with PKH67 and observed under confocal microscopy after the 2 week culture period. The GAG content significantly increased compared with the degeneration control when degenerate discs were treated with MSCs, Link N, or a combination of both Link N and MSCs. Histological analysis revealed that the newly synthesized proteoglycan was able to diffuse throughout the ECM and restore tissue content even in areas remote from the cells. The quantity of extractable type II collagen was also increased when the degenerate discs were treated with MSCs and Link N, either alone or together. MSCs survived, integrated in the tissue, and were found distributed throughout the NP after the 2 week culture period. MSCs and Link N can restore GAG content in degenerate discs, when administered separately or together. Treatment with MSCs and Link N can also increase the expression of type II collagen. The results support the concept that biological repair of disc degeneration is feasible, and that the administration of either MSCs or Link N has therapeutic potential in early stages of the disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Link N and Mesenchymal Stem Cells Can Induce Regeneration of the Early Degenerate Intervertebral Disc

Mwale

Wang

Roughley

et al. 2014

Tissue Engineering Part A

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show abstract

“…Cryptic peptides [64] which recruit resident progenitor cells to sites of tissue damage to effect ECM/remodelling to promote repair processes have been described [65] and of relevance to repair of the degenerate IVD. Link-N, a cryptic fragment of linkprotein has been applied to a number of IVD studies and shown to stimulate the resident IVD cell populations as well as progenitor stem cells to upregulate production of collagen and aggrecan and stimulate repair of the degenerate IVD [66][67][68][69][70][71][72]. Future studies will hopefully uncover basic data applicable to the application of the resident progenitor stem cell population we have observed as a therapeutic cell type.…”

Section: Spine Research Issn 2471-8173mentioning

confidence: 99%

A Global Pictorial Assessment of the Intervertebral Disc Cell in Several Species Reveals a Remarkable Biodiversity in this Cell Type which should be taken into Account in Experimental Studies on Intervertebral Disc Repair

Melrose¹

2016

Spine Res

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“…Hence, Link N is indicated that possesses growth factor -like property. 14 Recently, more and more studies try to use mesenchymal stem cells (MSCs) for further effective treatment, including to enhance TMJ repair. 15,16 MSCs are multipotent stem cells.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Link N on Mesenchymal Stem Cell Under IL-1β Stimulation

Yang¹,

Wang²,

Hsu

et al. 2017

UIP HEATH MED

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Objective: Temporomandibular joint (TMJ) arthritis can be induced by several inflammatory cytokines that may affect extracellular matrix (ECM) component expression. Link-N is exfoliated from Link protein (LP) which is one of the ECM components. It possesses ability to stimulate synthesis of ECM component. However, information regarding the potential of Link-N to modulate inflammatory process remains lacking. Methods:Mesenchymal stem cells (MSCs) derived from oral adipose tissues were isolated from dental operation under regulation of IRB, and were stained by the early stage stem cell markers (OCT4, NANOG, REX1, and SOX2). MSCs were under IL-1β (1ng/ml) or Link-N (1μg/ml) stimulation at 24 hours and 96 hours. Cell supernatant were collected then concentration quantification of cytokines was performed by Luminex multiplex assays. Results:MSCs showed the early stage stem cell markers. IP-10 and IL-6 increased significantly under IL1βstimulation, but Link-N did not. The protection marker, IL-4, IL-13 elevated during Link-N treatment compared with only IL-1β stimulation at 24, 96 hours. The chondrogenesis regulator, TGF-β, increased significantly compared with only IL-1β stimulation at 96 hours. Conclusion:During inflammation, Link-N can inhibit inflammatory response. On the other hand, it can enhance protection marker and chondrogenesis regulator expression. Link N may provide additional effect to assist joint repair.

show abstract

Link Protein N-terminal Peptide Binds to Bone Morphogenetic Protein (BMP) Type II Receptor and Drives Matrix Protein Expression in Rabbit Intervertebral Disc Cells

Cited by 39 publications

References 40 publications

Link N and Mesenchymal Stem Cells Can Induce Regeneration of the Early Degenerate Intervertebral Disc

Link N and Mesenchymal Stem Cells Can Induce Regeneration of the Early Degenerate Intervertebral Disc

A Global Pictorial Assessment of the Intervertebral Disc Cell in Several Species Reveals a Remarkable Biodiversity in this Cell Type which should be taken into Account in Experimental Studies on Intervertebral Disc Repair

The Effect of Link N on Mesenchymal Stem Cell Under IL-1β Stimulation

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