Inhibition of NF-κB Signaling-Mediated Crosstalk Between Macrophages and Preosteoblasts by Metformin Alleviates Trauma-Induced Heterotopic Ossification

Jia, Hongyan; Chen, Jie; Fan, Jun; Tang, Zhimin; Zhou, Wenwen; Lin, Hui

doi:10.1007/s10753-023-01817-2

Cited by 7 publications

(36 citation statements)

References 42 publications

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“…The procedures were performed strictly in accordance with National Institutes of Health Guide for Animal Care. The mouse traumatic HO model was established by performing Achilles tenotomy and burn injury, which was reported in our previously study 3,34 . In brief, C57BL/6 female mice aged 6–8 weeks old underwent an Achilles tenotomy on the left hind limb under general anaesthesia.…”

Section: Methodsmentioning

confidence: 99%

“…Heterotopic ossification (HO) refers to the aberrant formation of ectopic bone in muscle and soft tissue, and often occurs following severe trauma, burns, amputation, hip replacements, etc 1 . HO causes chronic pain, joint ankylosis and immobilisation 2,3 . Additionally, progressive HO in soft tissues has been found in one genetic disease called fibrodysplasia ossificans progressiva (FOP, OMIM#135100), which arises from activating mutations in ALK2 .…”

Section: Introductionmentioning

confidence: 99%

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Berberine and aspirin prevent traumatic heterotopic ossification by inhibition ofBMPsignalling pathway and osteogenic differentiation

Fan,

Gao,

Chen

et al. 2023

J Cellular Molecular Medi

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Heterotopic ossification (HO) is a pathological process that often occurs in soft tissues following severe trauma. There is no effective therapy for HO. The BMP signalling pathway plays an essential role in the pathogenesis of HO. Our previous study showed that AMPK negatively regulates the BMP signalling pathway and osteogenic differentiation. The present study aims to study the effect of two AMPK activators berberine and aspirin on osteogenic differentiation and HO induced by traumatic injury. The effects of two AMPK activators, berberine and aspirin, on BMP signalling and osteogenic differentiation were measured by western blot, ALP and Alizarin red S staining in C3H10T1/2 cells. A mouse model with Achilles tenotomy was employed to assess the effects of berberine and aspirin on HO using μCT and histological analysis. First, our study showed that berberine and aspirin inhibited phosphorylation of Smad1/5 induced by BMP6 and the inhibition was attributed to the down‐regulation of ALK2 expression. Second, the combination of berberine and aspirin yielded more potent effects on BMP signalling. Third, we further found that there was an additive effect of berberine and aspirin combination on osteogenic differentiation. Finally, we found that berberine and aspirin blocked trauma‐induced ectopic bone formation in mice, which may be through suppression of phosphorylation of Smad1/5 in injured tissues. Collectively, these findings indicate that berberine and aspirin inhibit osteogenic differentiation in C3H10T1/2 cells and traumatic HO in mice, possibly through the down‐regulation of the BMP signalling pathway. Our study sheds a light on prevention and treatment of traumatic HO using AMPK pharmacological activators berberine and aspirin.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Berberine and aspirin prevent traumatic heterotopic ossification by inhibition ofBMPsignalling pathway and osteogenic differentiation

Fan,

Gao,

Chen

et al. 2023

J Cellular Molecular Medi

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“…In general, HO requires three events, including inflammation, chondrogenic differentiation in mesenchymal stem cells (MSCs) [ 5 ], and the establishment of a suitable microenvironment [ 6 , 7 ]. According to numerous studies, macrophages also play a significant role in regulating the many facets of HO development [ 8 ]. Specifically, the molecular mechanisms underlying HO involve several signalling pathways mediated by BMP, HIF1-α (hypoxia inducible factor 1-α), TGF-β (transforming growth factor-β), and RAR (retinoic acid receptor) [ 3 ].…”

Section: Heterotopic Ossification (Ho)mentioning

confidence: 99%

“…Specifically, the molecular mechanisms underlying HO involve several signalling pathways mediated by BMP, HIF1-α (hypoxia inducible factor 1-α), TGF-β (transforming growth factor-β), and RAR (retinoic acid receptor) [ 3 ]. Additionally, an increasing number of studies have shown the involvement of nuclear transcription factor kappa B (NF-κB) in multiple cellular processes, especially those that can facilitate inflammation and subsequent bone formation [ 8 , 9 ].…”

Section: Heterotopic Ossification (Ho)mentioning

confidence: 99%

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Role of the NF-kB signalling pathway in heterotopic ossification: biological and therapeutic significance

Liu,

Zhao,

Pei

et al. 2024

Cell Commun Signal

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Heterotopic ossification (HO) is a pathological process in which ectopic bone develops in soft tissues within the skeletal system. Endochondral ossification can be divided into the following types of acquired and inherited ossification: traumatic HO (tHO) and fibrodysplasia ossificans progressiva (FOP). Nuclear transcription factor kappa B (NF-κB) signalling is essential during HO. NF-κB signalling can drive initial inflammation through interactions with the NOD‐like receptor protein 3 (NLRP3) inflammasome, Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK). In the chondrogenesis stage, NF-κB signalling can promote chondrogenesis through interactions with mechanistic target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/AKT (protein kinase B, PKB) and other molecules, including R-spondin 2 (Rspo2) and SRY-box 9 (Sox9). NF-κB expression can modulate osteoblast differentiation by upregulating secreted protein acidic and rich in cysteine (SPARC) and interacting with mTOR signalling, bone morphogenetic protein (BMP) signalling or integrin-mediated signalling under stretch stimulation in the final osteogenic stage. In FOP, mutated ACVR1-induced NF-κB signalling exacerbates inflammation in macrophages and can promote chondrogenesis and osteogenesis in mesenchymal stem cells (MSCs) through interactions with smad signalling and mTOR signalling. This review summarizes the molecular mechanism of NF-κB signalling during HO and highlights potential therapeutics for treating HO.

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Heterotopic ossification following total hip arthroplasty. Which is the predominant risk factor: surgical approach or post-operative prophylaxis?

Wang,

Zhi

2024

International Orthopaedics (SICOT)

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Inhibition of NF-κB Signaling-Mediated Crosstalk Between Macrophages and Preosteoblasts by Metformin Alleviates Trauma-Induced Heterotopic Ossification

Cited by 7 publications

References 42 publications

Berberine and aspirin prevent traumatic heterotopic ossification by inhibition ofBMPsignalling pathway and osteogenic differentiation

Berberine and aspirin prevent traumatic heterotopic ossification by inhibition ofBMPsignalling pathway and osteogenic differentiation

Role of the NF-kB signalling pathway in heterotopic ossification: biological and therapeutic significance

Heterotopic ossification following total hip arthroplasty. Which is the predominant risk factor: surgical approach or post-operative prophylaxis?

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