Macrophage migration inhibitory factor may contribute to hypertrophy of lumbar ligamentum flavum in type 2 diabetes mellitus

Lu, Qilin; Wang, Xiaozhen; Xie, Wei; Chen, Xiongwei; Zhu, Yuan Xiao; Li, Xugui

doi:10.1097/cm9.0000000000000680

Cited by 6 publications

(5 citation statements)

References 4 publications

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“…Previous studies have shown that LFH plays a key role in the pathogenesis of LSCS 5 , 26 . Although several studies have investigated the mechanisms of LFH at the cellular and molecular levels, the precise pathomechanism has not been fully elucidated 2 , 27 , 28 . In the current study, a novel bipedal standing mouse model was established 29 .…”

Section: Discussionmentioning

confidence: 99%

“…LSCS manifests as hypertrophy of the elements surrounding the spinal canal, including the ligamentum flavum (LF), joint osteophytes, intervertebral disc, and joint capsule, which narrows the available space for the dural sac as well as its neuronal contents. Among them, ligamentum flavum hypertrophy (LFH) is highly correlated with LSCS pathogenesis 2 , 3 . LFH tissue is characterized by altered arrangements of fibers in patients with LSCS.…”

Section: Introductionmentioning

confidence: 99%

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Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling

Lian

Liu

et al. 2022

Exp Mol Med

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Ligamentum flavum hypertrophy (LFH) is a major cause of lumbar spinal canal stenosis (LSCS). The pathomechanisms for LFH have not been fully elucidated. Isobaric tags for relative and absolute quantitation (iTRAQ) technology, proteomics assessments of human ligamentum flavum (LF), and successive assays were performed to explore the effect of clusterin (CLU) upregulation on LFH pathogenesis. LFH samples exhibited higher cell positive rates of the CLU, TGF-β1, α-SMA, ALK5 and p-SMAD3 proteins than non-LFH samples. Mechanical stress and TGF-β1 initiated CLU expression in LF cells. Notably, CLU inhibited the expression of mechanical stress-stimulated and TGF-β1-stimulated COL1A2 and α-SMA. Mechanistic studies showed that CLU inhibited mechanical stress-stimulated and TGF-β1-induced SMAD3 activities through suppression of the phosphorylation of SMAD3 and by inhibiting its nuclear translocation by competitively binding to ALK5. PRKD3 stabilized CLU protein by inhibiting lysosomal distribution and degradation of CLU. CLU attenuated mechanical stress-induced LFH in vivo. In summary, the findings showed that CLU attenuates mechanical stress-induced LFH by modulating the TGF-β1 pathways in vitro and in vivo. These findings imply that CLU is induced by mechanical stress and TGF-β1 and inhibits LF fibrotic responses via negative feedback regulation of the TGF-β1 pathway. These findings indicate that CLU is a potential treatment target for LFH.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling

Lian

Liu

et al. 2022

Exp Mol Med

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“…In fact, neovascularization is a prominent histological characteristic of tendinopathy [1,5,17]. Recent research has also revealed a positive correlation between MIF concentration in the lumbar ligamentum flavum and its thickness in patients with type 2 diabetes and spinal stenosis [33]. However, the effect of MIF on tendon homeostasis in diabetic conditions has not been established yet.…”

Section: Discussionmentioning

confidence: 99%

Altered Differentiation of Tendon-Derived Stem Cells in Diabetic Conditions Mediated by Macrophage Migration Inhibitory Factor

Kim

Noh

Chae

et al. 2021

IJMS

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The purpose of our study was to evaluate the role of macrophage migration inhibitory factor (MIF) in the differentiation of tendon-derived stem cells (TdSCs) under hyperglycemic conditions. In the in vivo experiment, rats were classified into diabetic (DM) and non-DM groups depending on the intraperitoneal streptozotocin (STZ) or saline injection. Twelve-week after STZ injection, the supraspinatus tendon was harvested and prepared for histological evaluation and real-time reverse transcription polymerase chain reaction for osteochondrogenic (aggrecan, BMP-2, and Sox9) and tenogenic (Egr1, Mkx, scleraxis, type 1 collagen, and Tnmd) markers. For the in vitro experiment, TdSCs were isolated from healthy rat Achilles tendons. Cultured TdSCs were treated with methylglyoxal and recombinant MIF or MIF gene knockdown to determine the effect of hyperglycemic conditions and MIF on the differentiation function of TdSCs. These conditions were classified into four groups: hyperglycemic-control group, hyperglycemic-recombinant-MIF group, hyperglycemic-knockdown-MIF group, and normal-control group. The mRNA expression of osteochondrogenic and tenogenic markers was compared among the groups. In the in vivo experiment, the mRNA expression of all osteochondrogenic and tenogenic differentiation markers in the DM group was significantly higher and lower than that in the non-DM group, respectively. Similarly, in the in vitro experiments, the expression of all osteochondrogenic and tenogenic differentiation markers was significantly upregulated and downregulated, respectively, in the hyperglycemic-control group compared to that in the normal-control group. The hyperglycemic-knockdown-MIF group demonstrated significantly decreased expression of all osteochondrogenic differentiation markers and increased expression of only some tenogenic differentiation markers compared with the hyperglycemic-control group. In contrast, the hyperglycemic-recombinant-MIF group showed significantly increased expression of all osteochondrogenic differentiation markers, but no significant difference in any tenogenic marker level, compared to the hyperglycemic-control group. These results suggest that tendon homeostasis could be affected by hyperglycemic conditions, and MIF appears to alter the differentiation of TdSCs via enhancement of the osteochondrogenic differentiation in hyperglycemic conditions. These are preliminary findings, and must be confirmed in a further study.

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“…Diabetes mellitus type 2 (T2DM) is a systemic and metabolic disease with hyperglycemia caused by genetic and environmental factors [ 1 , 2 ]. The long-term higher hyperglycemia of diabetic patients is mainly caused by the defect of insulin secretion or the impaired biological function of insulin (insulin resistance), which leads to the occurrence of serious complications and the dysfunction of the main organs [ 3 , 4 , 5 ]. Drug delivery systems mainly include injection administration and oral administration.…”

Section: Introductionmentioning

confidence: 99%

Chitosan Derivative-Based Microspheres Loaded with Fibroblast Growth Factor for the Treatment of Diabetes

Chen

Wang

et al. 2023

Polymers

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Diabetes mellitus type 2 (T2DM) is a disease caused by genetic and environmental factors, and the main clinical manifestation is hyperglycemia. Currently, insulin injections are still the first-line treatment for diabetes. However, repeated injections may cause insulin resistance, hypoglycemia, and other serious side effects. Thus, it is imperative to develop new diabetes treatments. Protein-based diabetes drugs, such as fibroblast growth factor-21 (FGF-21), have a longer-lasting glycemic modulating effect with high biosafety. However, the instability of these protein drugs limits their applications. In this study, we extract protein hypoglycemic drugs with oral and injectable functions. The FGF-21 analog (NA-FGF) was loaded into the chitosan derivative-based nanomaterials, N-2-Hydroxypropyl trimethyl ammonium chloride chitosan/carboxymethyl chitosan (N-2-HACC/CMCS), to prepare NA-FGF-loaded N-2-HACC/CMCS microspheres (NA-FGF-N-2-HACC/CMCS MPs). It was well demonstrated that NA-FGF-N-2-HACC/CMCS MPs have great biocompatibility, biostability, and durable drug-release ability. In addition to injectable drug delivery, our prepared microspheres were highly advantageous for oral administration. The in vitro and in vivo experimental results suggested that NA-FGF-N-2-HACC/CMCS MPs could be used as a promising candidate and universal nano-delivery system for both oral and injectable hypoglycemic regulation.

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Macrophage migration inhibitory factor may contribute to hypertrophy of lumbar ligamentum flavum in type 2 diabetes mellitus

Cited by 6 publications

References 4 publications

Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling

Clusterin negatively modulates mechanical stress-mediated ligamentum flavum hypertrophy through TGF-β1 signaling

Altered Differentiation of Tendon-Derived Stem Cells in Diabetic Conditions Mediated by Macrophage Migration Inhibitory Factor

Chitosan Derivative-Based Microspheres Loaded with Fibroblast Growth Factor for the Treatment of Diabetes

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