Estrogen Inhibits RANKL-Induced Osteoclastic Differentiation by Increasing the Expression of TRPV5 Channel

Chen, Fangjing; Ouyang, Yueping; Ye, Tianwen; Ni, Bin; Chen, Aimin

doi:10.1002/jcb.24700

Cited by 44 publications

(36 citation statements)

References 27 publications

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“…25 Estrogen also inhibits RANKLinduced osteoclastic differentiation. 26 Another estrogenic effect against bone loss is the upregulation of osteoprotegerin (OPG) secretion by osteoblasts 27 and marrow stromal cells. 3 Moreover, estrogen seems to inhibit bone resorption via upregulation of interleukin-10 (IL-10) 28 and semaphorin 3A (Sema3A).…”

Section: Introductionmentioning

confidence: 99%

ST2 regulates bone loss in a site‐dependent and estrogen‐dependent manner

Macari

Madeira

Lima

et al. 2018

J of Cellular Biochemistry

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Interleukin-33 (IL-33) and its receptor, ST2, are implicated in bone remodeling. The lack of estrogen after menopause results in an accelerated bone loss. Here we investigated the role of ST2 in the bone loss induced by estrogen deficiency. ST2-deficient mice (ST2 ) and their littermates (wildtype [WT]) were ovariectomized (OVX), while ovary-intact mice were used as controls. Bone sites were analyzed by microcomputed tomography, histomorphometry, and quantitative real-time polymerase chain reaction (qPCR). Deletion of IL-33 or ST2 resulted in a similar bone loss in the femur and maxilla. Ovariectomy in WT mice caused bone loss in the same areas. The lack of ST2 in OVX mice did not alter bone remodeling in the femur but prevented bone loss in the maxilla. Consistently, ovariectomy increased the IL-33 messenger RNA (mRNA) levels in the maxilla but not in the femur. Under mechanical stimulation, ovariectomy and ST2 deletion independently increased bone remodeling induced by orthodontic tooth movement, which was also associated with a greater number of osteoclasts and a reduced number of osteoblasts in the maxillary bone. ST2 OVX mice, however, displayed twice as many osteoblasts as that of WT OVX mice. Ovariectomy and ST2 deletion differently altered the cytokine mRNA levels in the maxilla. Remarkably, interleukin-10 expression was decreased in both WT OVX and ST2 mice, and this reduction was completely restored in ST2 OVX mice. The results demonstrate that estrogen and IL33/ST2 independently protect against bone loss. However, the ovariectomy-induced bone loss is IL-33/ST2-dependent in the maxilla but not in the femur, indicating a bimodal and site-specific role of ST2 in bone remodeling.

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Section: Introductionmentioning

confidence: 99%

ST2 regulates bone loss in a site‐dependent and estrogen‐dependent manner

Macari

Madeira

Lima

et al. 2018

J of Cellular Biochemistry

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“…AP-1 is composed of Fga (c-Fos, FosB, Fra-I, and Gra-2) and Jun (c-Jun, JunB, and JunD). c-Fos and c-Jun were reported to be critical for transcriptional activation of NFATc1 in RANKL-induced osteoclastogenesis [47–50]. Thus, we propose that inhibition of RANKL-induced c-Fos and c-Jun expression by Rg1 is a relevant factor influencing the suppression of downstream NFATc1 signaling pathways.…”

Section: Discussionmentioning

confidence: 83%

“…Dexamethasone increases osteoclast formation and lacunar resorption in the presence of M-CSF and RANKL in vitro [49]; on the contrary, Rg1, which is the functional ligand of glucocorticoid receptors [16, 24], inhibited osteoclastogenesis in RANKL-induced RAW264.7 cells. This is probably because Rg1 possesses oestrogen-like effects which causes the decrease in osteoclastogenesis [17, 50]. A further study is certainly required.…”

Section: Discussionmentioning

confidence: 99%

The Study of Mechanisms of Protective Effect of Rg1 against Arthritis by Inhibiting Osteoclast Differentiation and Maturation in CIA Mice

Fan

Yin

2014

Mediators of Inflammation

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Ginsenoside Rg1 is a natural product extracted from Panax ginseng C.A. Although Rg1 protects tissue structure and functions by inhibiting local inflammatory reaction, the mechanism remains poorly understood. In vitro, Rg1 dose-dependently inhibited TRAP activity in receptor activator of nuclear factor-κB ligand- (RANKL-) induced osteoclasts and decreased the number of osteoclasts and osteoclast resorption area. Rg1 also significantly inhibited the RANK signaling pathway, including suppressing the expression of Trap, cathepsin K, matrix metalloproteinase 9 (MMP9), and calcitonin receptor (CTR). In vivo, Rg1 dramatically decreased arthritis scores in CIA mice and effectively controlled symptoms of inflammatory arthritis. Pathologic analysis demonstrated that Rg1 significantly attenuated pathological changes in CIA mice. Pronounced reduction in synovial hyperplasia and inflammatory cell invasion were observed in CIA mice after Rg1 therapy. Alcian blue staining results illustrated that mice treated with Rg1 had significantly reduced destruction in the articular cartilage. TRAP and cathepsin K staining results demonstrated a significant reduction of numbers of OCs in the articular cartilage in proximal interphalangeal joints and ankle joints in Rg1-treated mice. In summary, this study revealed that Rg1 reduced the inflammatory destruction of periarticular bone by inhibiting differentiation and maturation of osteoclasts in CIA mice.

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“…Loss of TRPV5 function results in abnormal ionocyte proliferation and increased colon cancer risk [8]. TRPV5 may contribute to the process of estrogen-inhibited osteoclastogenesis and bone resorption activity by mediating extracellular Ca 2+ [9]. The increase in intracellular Ca 2+ levels can result activation of the Ca 2+ sensor protein calmodulin and combined target proteins to form the Ca 2+ /calmodulin complex [10].…”

Section: Introductionmentioning

confidence: 99%

Transient Receptor Potential Channel, Vanilloid 5, Induces Chondrocyte Apoptosis in a Rat Osteoarthritis Model Through the Mediation of Ca2+ Influx

Wei

Zheng

Guo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chondrocyte apoptosis is the most common pathological feature in cartilage in osteoarthritis (OA). Transient receptor potential channel vanilloid 5 (TRPV5) is important in regulating calcium ion (Ca²⁺) influx. Accumulating evidences suggest that Ca²⁺ is a major intracellular second messenger that can trigger cell apoptosis. Therefore, we investigate the potential role of TRPV5 in mediating Ca²⁺ influx to promote chondrocyte apoptosis in OA. Methods: The monoiodoacetic acid (MIA)-induced rat OA model was assessed by macroscopic and radiographic analyses. Calmodulin protein immunolocalization was detected by immunohistochemistry. The mRNA and protein level of TRPV5, calmodulin and cleaved caspase-8 in articular cartilage were assessed by real time polymerase chain reaction and western blotting. Primary chondrocytes were isolated and cultured in vitro. TRPV5 small interfering RNA was used to silence TRPV5 in chondrocytes. Then, calmodulin and cleaved caspase-8 were immunolocalized by immunofluorescence in chondrocyte. Fluo-4AM staining was used to assess intracellular Ca²⁺ to reflect TRPV5 function of mediation Ca²⁺ influx. Annexin V-fluorescein isothiocyanatepropidium iodide flow cytometric analysis was performed to determine chondrocytes apoptosis. Western blotting techniques were used to measure the apoptosis-related proteins in chondrocyte level. Results: Here, we reported TRPV5 was up-regulated in MIA-induced OA articular cartilage. Ruthenium red (a TRPV5 inhibitor) can relieve progression of joint destruction in vivo which promoted us to demonstrate the effect of TRPV5 in OA. We found that TRPV5 had a specific role in mediating extracellular Ca²⁺ influx leading to chondrocytes apoptosis in vitro. The apoptotic effect was inhibited even reversed by silencing TRPV5. Furthermore, we found that the increase Ca²⁺ influx triggered apoptosis by up-regulating the protein of death-associated protein, FAS-associated death domain, cleaved caspase-8, cleaved caspase-3, cleaved caspase-6, and cleaved caspase-7, and the up-regulated proteins were abolished by silencing TRPV5 or 1, 2-bis-(o-Aminophenoxy)-ethane-N,N,N’,N’-tetraacetic acid, tetraacetoxymethyl ester (a Ca²⁺ chelating agent). Conclusion: The up-regulated TRPV5 could used be as an initiating factor that induces extrinsic chondrocyte apoptosis via the mediation of Ca²⁺ influx. These findings suggested TRPV5 could be an intriguing mediator for drug target in OA.

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Estrogen Inhibits RANKL-Induced Osteoclastic Differentiation by Increasing the Expression of TRPV5 Channel

Cited by 44 publications

References 27 publications

ST2 regulates bone loss in a site‐dependent and estrogen‐dependent manner

ST2 regulates bone loss in a site‐dependent and estrogen‐dependent manner

The Study of Mechanisms of Protective Effect of Rg1 against Arthritis by Inhibiting Osteoclast Differentiation and Maturation in CIA Mice

Transient Receptor Potential Channel, Vanilloid 5, Induces Chondrocyte Apoptosis in a Rat Osteoarthritis Model Through the Mediation of Ca2+ Influx

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