Formononetin attenuates osteoclast differentiation and calcium loss by mediating transcription factor AP‐1 in type I diabetic mice

Jing, Wensen; Feng, Lei; Peng, Kan; Zhang, Weisong; Wang, Bo

doi:10.1002/jbt.23042

Cited by 7 publications

(6 citation statements)

References 39 publications

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“…In addition, in an aging society, aging‐related knee injury is a degenerative disease (Roos & Arden, 2016) and often results from other aging‐related diseases (such as diabetes‐induced osteoporosis and atherosclerosis (AS)). FMN has a good therapeutic effect, which was also reported in the existing research results (Jing et al, 2022; Ma et al, 2020). Therefore, FMN has advantages for nontraumatic, particularly aging‐related, degenerative knee injuries and has very good prospects for the treatment of such diseases.…”

Section: Discussionsupporting

confidence: 81%

Formononetin improves the inflammatory response and bone destruction in knee joint lesions by regulating the NF‐kB and MAPK signaling pathways

Zhang

et al. 2023

Phytotherapy Research

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Formononetin (FMN) is a phytoestrogen that belongs to the isoflavone family. It has antioxidant and anti-inflammatory effects, as well as, many other biological activities.Existing evidence has aroused interest in its ability to protect against osteoarthritis (OA) and promote bone remodeling. To date, research on this topic has not been thorough and many issues remain controversial. Therefore, the purpose of our study was to explore the protective effect of FMN against knee injury and clarify the possible molecular mechanisms. We found that FMN inhibited osteoclast formation induced by receptor activator of NF-κB ligand (RANKL). Inhibition of the phosphorylation and nuclear translocation of p65 in the NF-κB signaling pathway plays a role in this effect. Similarly, during the inflammatory response of primary knee cartilage cells activated by IL-1β, FMN inhibited the NF-κB signaling pathway and the phosphorylation of the ERK and JNK proteins in the MAPK signaling pathway to suppress the inflammatory response. In addition, in vivo experiments showed that both low-and high-dose FMN had a clear protective effect against knee injury in the DMM (destabilization of the medial meniscus) model, and the therapeutic effect of high-dose FMN was stronger. In conclusion, these studies provide evidence of the protective effect of FMN against knee injury.

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Section: Discussionsupporting

confidence: 81%

Formononetin improves the inflammatory response and bone destruction in knee joint lesions by regulating the NF‐kB and MAPK signaling pathways

Zhang

et al. 2023

Phytotherapy Research

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“…The downstream Fos family proteins (c-Fos, FosB, Fra-1, and Fra-2) form the activating protein-1 (AP-1) complex with the Jun family proteins (c-Jun, JunB, and JunD) and play a key role in osteoclast differentiation ( 54 , 55 ). Together with NFATc1 and other transcription factors, AP-1 can directly induce the expression of a variety of osteoclast-specific genes, such as CTSk , TRAP , and OSCAR , to achieve osteoclast differentiation ( 47 , 56 , 57 ). In our study, we found that MAI treatment decreased the RANKL, CTSK, OSCAR, OCSTAMP, and AP-1 at the gene level, while minimizing the osteoclast expression of the ankle in CIA mice.…”

Section: Discussionmentioning

confidence: 99%

Melittin acupoint injection in attenuating bone erosion in collagen-induced arthritis mice via inhibition of the RANKL/NF-κB signaling pathway

Liu,

Chen,

Yang

et al. 2023

Quant Imaging Med Surg

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Background Rheumatoid arthritis (RA) is an autoimmune disease leading to chronic joint inflammation. Bone erosion is the most serious pathological condition of RA and the main cause of joint deformities and disability. Melittin acupoint injection (MAI) is an effective traditional Chinese medicine (TCM) method for RA treatment. This study aimed to investigate the effect of MAI on RA bone erosion and to elucidate the underlying mechanism. Methods A collagen-induced arthritis (CIA) mouse model was established as the experimental subject. MAI was administrated once every other day for 28 days to mice with CIA. The effects of MAI on joint diseases were assessed by body weight, arthritis index (AI) score, swollen joint count (SJC) score, and hind paw thickness. Ankle radiological changes were captured by micro-computed tomography (micro-CT) and histological changes were observed by pathological staining. Organ histological changes, spleen index, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine (Crea) levels of serum were tested to evaluate the toxicity of MAI. Cytokine expression levels were confirmed by enzyme-linked immunosorbent assay (ELISA) to evaluate the immunity of CIA mice. Results MAI administration markedly improved the clinical signs of CIA in mice, including hind paw thickness, AI, and the number of swollen paw joints (most of them P<0.05 or even <0.01). According to histopathological analysis, MAI ameliorated inflammatory cell infiltration, synovial hyperplasia, pannus formation, and bone erosion (all P<0.01). Micro-CT and tartrate-resistant acid phosphatase (TRAP) staining (P<0.01) also revealed that MAI could relieve bone erosion via reducing the formation of osteoclasts. Not only could MAI relieve the immunological boost [P<0.05 for the high-dose MAI (HM) group], but also it had no liver or kidney side effects (P>0.05). In addition, it decreased the serum levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) and increased the serum levels of IL-4 and IL-10 (the majority of P<0.05 or even <0.01). Transcriptome sequencing results indicated that MAI affected the expression of osteoclast differentiation pathway genes, which was connected with the receptor activator of the nuclear factor κB ligand/nuclear factor kappa B (RANKL/NF-κB) pathway. Conclusions Based on our findings, MAI could suppress joint inflammation and inhibit RANKL/NF-κB-mediated osteoclast differentiation to rescue bone erosion in CIA mice, suggesting that MAI can be a potentially therapeutic substance for RA.

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“…Forward, 5′-CACTCCCACCCTGAGATTTGT-3′, Reverse, 5′-CCCCAGAGACATGATGAAGTCA-3′for TRAP; Forward, 5′-CGGGTTTCAACGCCGACTA-3′, Reverse, 5′-TTGGCACTAGAGACGGACAGA-3′for c-Fos; Forward, 5′-GGAGAGTCCGAGAATCGAGAT-3′, Reverse, 5′-TTGCAGCTAGGAAGTACGTCT-3′for Nuclear Factor Of Activated T Cells 1(NFATc1); 10 Forward, 5′-GGACCATCTTTCTGCTCACTCTG-3′, Reverse, 5′-GTTCACTACCTTATTGCCCTCCTG-3′for osteocalcin (OSC); Forward, 5′-CCTTCAAGGTTGTAGCCCTC-3′, Reverse, 5′-GGAGTAGTTCTCATCATTCCCG-3′for Runt-related transcription factor 2 (Runx2); Forward, 5′-TCCATCGAAGAATCAAAGCAGAG-3′, Reverse, 5′-CGAGAGTGTGGAAAGTGTGGAG-3′for Sialoprotein (Sia); Forward, 5′-AGGAGGCACAAAGAAGCCATACG-3′, Reverse, 5′-ATGCCTGCCTTGTACCACGAGC-3′for Osterix (Osx); Forward, 5′-TCATTCCCACGTTTTCACATTC-3′, Reverse, 5′-GTTGTTGTGAGCGTAATCTACC-3′for ALP; Forward, 5′-GTGTGGAGATGTGCCGCTATGAC-3′, Reverse, 5′-AGTCTCGGAGGTGCTCTTCAGTG-3′for JAK2; Forward, 5′-TGTCAGATCACATGGGCTAAAT-3′, Reverse, 5′-GGTCGATGATATTGTCTAGCCA-3′for STAT3; Forward, 5′-CGCTCTTCTGTCTACTGAACTTCGG-3′, https://doi.org/10.2147/IJN.S413692…”

Section: Real-time Quantitative Reverse Polymerase Chain Reaction (Qr...mentioning

confidence: 99%

“…The exosomes incorporate, transfer, stabilize, and protect themselves from degradation. [10][11][12] Lv et al 13 found that miR-181b-5p delivered by osteocyte-derived exosomes promotes human periodontal ligament stem cell proliferation via the phosphatase and tensin homolog(PTEN)/protein kinase B(PKB) pathway, suggesting that miRNAcarrying exosomes are crucial for bone remodeling in periodontitis. 14,15 Hu et al 3 illustrated that sympathetic neuro-stress could drive osteoblastic exosomal miR-21 transfer to regulate osteoclastogenesis.…”

Section: Introductionmentioning

confidence: 99%

Osteoclast-Derived Exosomal miR-5134-5p Interferes with Alveolar Bone Homeostasis by Targeting the JAK2/STAT3 Axis

Pan¹,

Zhang²,

Zhang³

et al. 2023

IJN

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Background: In chronic periodontitis, exosomes transport various informative substances between osteoclasts and osteoblasts in alveolar bone. Herein, we aimed to investigate the effect of exosomal micro-ribonucleic acid (miRNA/miR)-5134-5p derived from osteoclasts on osteoblastic proliferation and differentiation and the development of periodontitis in vivo and in vitro. Methods:The effects of OC-Exos on the proliferation and differentiation of osteoblasts were identified by Real-time quantitative reverse polymerase chain reaction (qRT-PCR), Western blot(WB), alkaline phosphatase(ALP) staining, etc. Exosomal miRNA expression was analyzed by sequencing. The sites of miRNA action were predicted through TargetScan and tested by double luciferase assay. After transfecting miR-5134-5p mimic/inhibitor into osteoblasts, we measured the proliferation and differentiation of osteoblasts by ALP staining and WB, etc. Furthermore, OC-Exos were injected into the gingival sulcus at the ligation site. Inflammation was observed by Hematoxylin-eosin (H&E) staining, the expression of inflammatory factors were detected by qRT-PCR, the resorption of alveolar bone was observed by Micro CT. Results: Osteoblastic proliferation and differentiation were negatively regulated by OC-Exos in vitro. miRNA sequencing analysis revealed that miR-5134-5p expression was significantly elevated in OC-Exos, which also increased in osteoblasts following OC-Exo intervention. The dual-luciferase assay revealed that miR-5134-5p and Janus kinase 2 (JAK2) had binding sites. miR-5134-5p-mimics could upregulate miR-5134-5p expression in osteoblasts while downregulating Runt-related transcription factor 2(Runx2), phosphorylated-JAK2 (p-JAK2), and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) expression and inhibited osteogenic differentiation. However, miR-5134-5p-inhibitor had the opposite effect. In vivo, the OC-Exo group demonstrated morphological disruption of periodontal tissue, massive inflammatory cell infiltration, upregulation of inflammatory factors mRNA expression, a significant decrease in BV/TV, and an increase in the cementoenamel junction and alveolar bone crest distance. Conclusion: Osteoclast-derived exosomal miR-5134-5p inhibits osteoblastic proliferation and differentiation via the JAK2/STAT3 pathway. OC-Exos exacerbate periodontal tissue inflammation and accelerate alveolar bone resorption in mice with experimental periodontitis.

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Formononetin attenuates osteoclast differentiation and calcium loss by mediating transcription factor AP‐1 in type I diabetic mice

Cited by 7 publications

References 39 publications

Formononetin improves the inflammatory response and bone destruction in knee joint lesions by regulating the NF‐kB and MAPK signaling pathways

Formononetin improves the inflammatory response and bone destruction in knee joint lesions by regulating the NF‐kB and MAPK signaling pathways

Melittin acupoint injection in attenuating bone erosion in collagen-induced arthritis mice via inhibition of the RANKL/NF-κB signaling pathway

Osteoclast-Derived Exosomal miR-5134-5p Interferes with Alveolar Bone Homeostasis by Targeting the JAK2/STAT3 Axis

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