Osteoprotegerin Expressed by Osteoclasts

Kang, Ji-Hyoun; Ko, Hyun-Mi; Moon, Jung-Sun; Yoo, H.I.; Jung, Jae-Youn; Kim, M.S.; Koh, Joon; Kim, W.J.; Kim, S.H.

doi:10.1177/0022034514552677

Cited by 33 publications

(12 citation statements)

References 36 publications

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“…5A, Trap , Ctsk , and c-Fos expression are significantly downregulated in the presence of CTHRC1 on days 4, 7, and 9 of differentiation. Although osteoblasts and osteocytes are considered major sources of Opg , which functions as a decoy receptor for RANKL , it was recently demonstrated that osteoclasts also express Opg (15). Interestingly, rather than an upregulation we observed a transient downregulation of Opg at day 2 of differentiation.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of osteoclast differentiation and collagen antibody-induced arthritis by CTHRC1

Jin

Stohn

Wang

et al. 2017

Bone

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Collagen triple helix repeat-containing1 (Cthrc1) has previously been implicated in osteogenic differentiation and positive regulation of bone mass, however, the underlying mechanisms remain unclear. Here we characterized the bone phenotype of a novel Cthrc1 null mouse strain using bone histomorphometry, μCT analysis and functional readouts for bone strength. In male Cthrc1 null mice both trabecular bone as well as cortical bone formation was impaired, whereas in female Cthrc1 null mice only trabecular bone parameters were altered. Novel and highly specific monoclonal antibodies revealed that CTHRC1 is expressed by osteocytes and osteoblasts, but not osteoclasts. Furthermore, Cthrc1 null mice exhibited increased bone resorption with increased number of osteoclast and increased osteoclast activity together with enhanced expression of osteoclastogenic genes such as c-Fos, Rankl, Trap, and Nfatc1. Differentiation of bone marrow-derived monocytes isolated from Cthrc1 null mice differentiated into osteoclasts as effectively as those from wildtype mice. In the presence of CTHRC1 osteoclastogenic differentiation of bone marrow-derived monocytes was dramatically inhibited as was functional bone resorption by osteoclasts. This process was accompanied by downregulation of osteoclastogenic marker genes, indicating that extrinsically derived CTHRC1 is required for such activity. In vitro, CTHRC1 had no effect on osteogenic differentiation of bone marrow stromal cells, however, calvarial osteoblasts from Cthrc1 null mice exhibited reduced osteogenic differentiation compared to osteoblasts from wildtypes. In a collagen antibody-induced arthritis model Cthrc1 null mice suffered significantly more severe inflammation and joint destruction than wildtypes, suggesting that CTHRC1 expressed by the activated synoviocytes has anti-inflammatory effects. Mechanistically, we found that CTHRC1 inhibited NFκB activation by preventing IκBα degradation while also inhibiting ERK1/2 activation. Collectively our studies demonstrate that CTHRC1 secreted from osteocytes and osteoblasts functions as an inhibitor of osteoclast differentiation via inhibition of NFκB-dependent signaling. Furthermore, our data suggest that CTHRC1 has potent anti-inflammatory properties that limit arthritic joint destruction.

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Section: Resultsmentioning

confidence: 99%

Inhibition of osteoclast differentiation and collagen antibody-induced arthritis by CTHRC1

Jin

Stohn

Wang

et al. 2017

Bone

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“…A statistical reduction of IL-6 gene expression and protein levels were found after treatment with the chloroform fraction (CLF). The higher expression levels of IL-6 in untreated periodontal disease might induce an increase in matrix metalloproteinases (MMPs) that are related to tissue destruction [ 36 , 37 ]. IL-6 has been reported as a principal regulator in the acute phase of inflammation and may promote osteoclastogenesis by increasing tRANKL expression [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Malva sylvestris Inhibits Inflammatory Response in Oral Human Cells. An In Vitro Infection Model

et al. 2015

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The aim of this study was to investigate the in vitro anti-inflammatory activity of Malva sylvestris extract (MSE) and fractions in a co-culture model of cells infected by Aggregatibacter actinomycetemcomitans. In addition, we evaluated the phytochemical content in the extract and fractions of M. sylvestris and demonstrated that polyphenols were the most frequent group in all samples studied. An in vitro dual-chamber model to mimic the periodontal structure was developed using a monolayer of epithelial keratinocytes (OBA-9) and a subepithelial layer of fibroblasts (HGF-1). The invasive periodontopathogen A. actinomycetemcomitans (D7S-1) was applied to migrate through the cell layers and induce the synthesis of immune factors and cytokines in the host cells. In an attempt to analyze the antimicrobial properties of MSE and fractions, a susceptibility test was carried out. The extract (MIC 175 μg/mL, MBC 500μg/mL) and chloroform fraction (MIC 150 μg/mL, MBC 250 μg/mL) were found to have inhibitory activity. The extract and all fractions were assessed using a cytotoxicity test and results showed that concentrations under 100 μg/mL did not significantly reduce cell viability compared to the control group (p > 0.05, viability > 90%). In order to analyze the inflammatory response, transcriptional factors and cytokines were quantified in the supernatant released from the cells. The chloroform fraction was the most effective in reducing the bacterial colonization (p< 0.05) and controlling inflammatory mediators, and promoted the down-regulation of genes including IL-1beta, IL-6, IL-10, CD14, PTGS, MMP-1 and FOS as well as the reduction of the IL-1beta, IL-6, IL-8 and GM-CSF protein levels (p< 0.05). Malva sylvestris and its chloroform fraction minimized the A. actinomycetemcomitans infection and inflammation processes in oral human cells by a putative pathway that involves important cytokines and receptors. Therefore, this natural product may be considered as a successful dual anti-inflammatory–antimicrobial candidate.

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“…We hypothesized that this different gene and protein expression was associated to the fact that OPG may play an autoregulatory role during osteoclastogenesis in an intrinsic mechanism that negatively regulate its expression. A negative feedback in osteoclastogenesis was already reported by Kang et al [37] who suggested that OPG, expressed by the osteoclasts themselves, may play an auto-regulatory role during osteoclastogenesis through the induction of apoptosis. However, despite our hypothesis on the possible autoregulatory role of OPG during osteoclastogenesis, this study underlined the presence of still numerous doubts regarding the serious question of how the OPG/RANKL/RANK or OPG/TRAIL/death receptor system interacts during osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 66%

An in vitro 3D bone metastasis model by using a human bone tissue culture and human sex-related cancer cells

et al. 2016

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One of the main limitations, when studying cancer-bone metastasis, is the complex nature of the native bone environment and the lack of reliable, simple, inexpensive models that closely mimic the biological processes occurring in patients and allowing the correct translation of results. To enhance the understanding of the mechanisms underlying human bone metastases and in order to find new therapies, we developed an in vitro three-dimensional (3D) cancer-bone metastasis model by culturing human breast or prostate cancer cells with human bone tissue isolated from female and male patients, respectively. Bone tissue discarded from total hip replacement surgery was cultured in a rolling apparatus system in a normoxic or hypoxic environment. Gene expression profile, protein levels, histological, immunohistochemical and four-dimensional (4D) micro-CT analyses showed a noticeable specificity of breast and prostate cancer cells for bone colonization and ingrowth, thus highlighting the species-specific and sex-specific osteotropism and the need to widen the current knowledge on cancer-bone metastasis spread in human bone tissues. The results of this study support the application of this model in preclinical studies on bone metastases and also follow the 3R principles, the guiding principles, aimed at replacing/reducing/refining (3R) animal use and their suffering for scientific purposes.

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Osteoprotegerin Expressed by Osteoclasts

Cited by 33 publications

References 36 publications

Inhibition of osteoclast differentiation and collagen antibody-induced arthritis by CTHRC1

Inhibition of osteoclast differentiation and collagen antibody-induced arthritis by CTHRC1

Malva sylvestris Inhibits Inflammatory Response in Oral Human Cells. An In Vitro Infection Model

An in vitro 3D bone metastasis model by using a human bone tissue culture and human sex-related cancer cells

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