Skeletal changes in osteoprotegerin and receptor activator of nuclear factor-κb ligand mRNA levels in primary hyperparathyroidism: effect of parathyroidectomy and association with bone metabolism

Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-κB ligand (RANKL)–induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKCα/βII, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis.

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Estrogen Receptor-Related Receptor α Impinges on the Estrogen Axis in Bone: Potential Function in Osteoporosis

Endocrinology ◽

10.1210/en.2002-220095 ◽

2002 ◽

Vol 143 (9) ◽

pp. 3658-3670 ◽

Cited By ~ 33

Author(s):

Edith Bonnelye ◽

Vanessa Kung ◽

Catherine Laplace ◽

Deborah L. Galson ◽

Jane E. Aubin

Keyword(s):

Estrogen Receptor ◽

Functional Role ◽

Nuclear Factor Κb ◽

Mrna Levels ◽

Nuclear Factor ◽

Post Surgery ◽

Rat Calvaria ◽

Receptor Activator

Abstract The orphan nuclear estrogen receptor-related receptor α (ERRα) is expressed by osteoblastic cells and plays a functional role in osteoprogenitor proliferation and differentiation. To dissect further the role of ERRα in bone, we investigated the effects of estrogen (E2) on ERRα both in vitro and in vivo. Chronic treatment of fetal rat calvaria cells with E2-stimulated bone nodule formation and up-regulated ERRα mRNA expression at early (10 h and d 8) but not later times in culture, suggesting a link between ERRα and E2 during osteoprogenitor proliferation. ERRα mRNA levels were significantly lower in ovariectomized adult rat bones vs. those of sham-operated rats early (1 d and 1 wk) post surgery, but levels returned to control levels thereafter. ERRα is also expressed in osteoclasts (tartrate-resistant acid phosphatase + multinucleated cells) in vivo and in vitro (RAW 264.7 cells) and ovariectomization lowered the OPG/receptor activator of nuclear factor κB ligand expression ratio. Down-regulation of ERRα expression via antisense treatment of rat calvaria cells not only inhibited osteogenesis but also increased adipocyte colony formation and changed the OPG/receptor activator of nuclear factor κB ligand ratio. These data suggest that ERRα is regulated by estrogen in bone in which it may play a functional role at several levels (osteoblasts, adipocytes, and osteoclasts) in E2 deficiency diseases such as osteoporosis.

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Evaluation of Isoflavones as Bone Resorption Inhibitors upon Interactions with Receptor Activator of Nuclear Factor-κB Ligand (RANKL)

Molecules ◽

10.3390/molecules25010206 ◽

2020 ◽

Vol 25 (1) ◽

pp. 206 ◽

Cited By ~ 7

Author(s):

Małgorzata Zakłos-Szyda ◽

Grażyna Budryn ◽

Joanna Grzelczyk ◽

Horacio Pérez-Sánchez ◽

Dorota Żyżelewicz

Keyword(s):

Bone Resorption ◽

In Silico ◽

Docking Simulation ◽

Nuclear Factor Κb ◽

Biochanin A ◽

Mrna Levels ◽

Nuclear Factor ◽

In Silico Docking ◽

Receptor Complexes ◽

Receptor Activator

Receptor activator of nuclear factor-κB ligand (RANKL) is a cytokine responsible for bone resorption. It binds its receptor RANK, which activates osteoporosis. High levels of osteoprotegerin (OPG) competitively binding RANKL limit formation of ligand-receptor complexes and enable bone mass maintenance. The new approach to prevent osteoporosis is searching for therapeutics that can bind RANKL and support OPG function. The aim of the study was to verify the hypothesis that isoflavones can form complexes with RANKL limiting binding of the cytokine to its receptor. Interactions of five isoflavones with RANKL were investigated by isothermal titration calorimetry (ITC), by in silico docking simulation and on Saos-2 cells. Daidzein and biochanin A showed the highest affinity for RANKL. Among studied isoflavones coumestrol, formononetin and biochanin A showed the highest potential for Saos-2 mineralization and were able to regulate the expression of RANKL and OPG at the mRNA levels, as well as osteogenic differentiation markers: alkaline phosphatase (ALP), collagen type 1, and Runt-related transcription factor 2 (Runx2). Comparison of the osteogenic activities of isoflavones showed that the use of physicochemical techniques such as ITC or in silico docking are good tools for the initial selection of substances showing a specific bioactivity.

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The Role of the Receptor Activator of Nuclear Factor-κB Ligand/Osteoprotegerin Cytokine System in Primary Hyperparathyroidism

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-1645 ◽

2008 ◽

Vol 93 (3) ◽

pp. 967-973 ◽

Cited By ~ 28

Author(s):

Inaam A. Nakchbandi ◽

Robert Lang ◽

Barbara Kinder ◽

Karl L. Insogna

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Primary Hyperparathyroidism ◽

Nuclear Factor Κb ◽

Type I ◽

Nuclear Factor ◽

Soluble Receptor ◽

Mineral Density ◽

Receptor Activator ◽

Markers Of Bone Resorption

Abstract Context: The mechanisms of action of PTH on bone in vivo remain incompletely understood. The objective of this investigation was to examine changes in serum levels of receptor activator of nuclear factor-κB ligand and osteoprotegerin (OPG) in primary hyperparathyroidism and their relationship to bone loss. Patients and Methods: Twenty-nine patients with primary hyperparathyroidism had baseline circulating soluble receptor activator of nuclear factor-κB ligand (sRANKL) and OPG measured. The relationship to biochemical markers of bone turnover and changes in bone mineral density over 2 yr was examined. Results: Baseline sRANKL levels were elevated (1.7 ± 0.1 pmol/liter), whereas OPG remained in the normal range (5.6 ± 0.4 pmol/liter). Circulating sRANKL did not correlate with PTH but did correlate with markers of bone resorption (urine deoxypyridinoline cross-links: r = 0.51, P < 0.01; serum N-telopeptide of type I collagen: r = 0.37, P < 0.05). Furthermore, sRANKL correlated with both IL-6 and IL-6 soluble receptor (IL-6sR) (r = 0.47, P < 0.05 and r = 0.55, P < 0.005, respectively). Serum sRANKL levels also correlated with bone loss at the total femur (r = −0.53, P < 0.01). Lastly, a high value of sRANKL in combination with values of IL-6 and IL-6sR in the upper quartile (sRANKL ≥ 1.81 pg/ml, IL −6 ≥ 11.8 pg/ml, and IL-6sR ≥ 45.6 ng/ml) defined a group of four women with significantly greater rates of bone loss at the total femur than the remaining patients (−2.7 ± 1.7% vs. +0.5 ± 0.3%; n = 4 vs. n = 19, P < 0.05). Conclusion: Determination of circulating levels of sRANKL may be useful in identifying patients with mild primary hyperparathyroidism at greater risk for bone loss. The fact that circulating sRANKL did not correlate with PTH but did correlate with markers of bone resorption suggests that skeletal responsiveness to PTH may differ in this disease.

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Schistosome infection promotes osteoclast-mediated bone loss

PLoS Pathogens ◽

10.1371/journal.ppat.1009462 ◽

2021 ◽

Vol 17 (3) ◽

pp. e1009462

Author(s):

Wei Li ◽

Chuan Wei ◽

Lei Xu ◽

Beibei Yu ◽

Ying Chen ◽

...

Keyword(s):

Bone Loss ◽

Bone Metabolism ◽

Cell Subset ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Skeletal System ◽

Schistosome Infection ◽

Prevent Bone Loss ◽

Follicular Helper ◽

Receptor Activator

Infection with schistosome results in immunological changes that might influence the skeletal system by inducing immunological states affecting bone metabolism. We investigated the relationships between chronic schistosome infection and bone metabolism by using a mouse model of chronic schistosomiasis, affecting millions of humans worldwide. Results showed that schistosome infection resulted in aberrant osteoclast-mediated bone loss, which was accompanied with an increased level of receptor activator of nuclear factor-κB (NF-κB) Ligand (RANKL) and decreased level of osteoprotegerin (OPG). The blockade of RANKL by the anti-RANKL antibody could prevent bone loss in the context of schistosome infection. Meanwhile, both B cells and CD4+ T cells, particularly follicular helper T (Tfh) cell subset, were the important cellular sources of RANKL during schistosome infection. These results highlight the risk of bone loss in schistosome-infected patients and the potential benefit of coupling bone therapy with anti-schistosome treatment.

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Co-activation of synovial fibroblasts by laminin-111 and transforming growth factor-β induces expression of matrix metalloproteinases 3 and 10 independently of nuclear factor-κB

Annals of the Rheumatic Diseases ◽

10.1136/ard.2007.073809 ◽

2007 ◽

Vol 67 (4) ◽

pp. 559-562 ◽

Cited By ~ 4

Author(s):

K Warstat ◽

T Pap ◽

G Klein ◽

S Gay ◽

W K Aicher

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Synovial Fibroblasts ◽

Transforming Growth Factor Β ◽

Nuclear Factor Κb ◽

Mrna Levels ◽

Nuclear Factor ◽

The Matrix ◽

Specific Tissue ◽

Significant Expression

We showed previously that the attachment of synovial fibroblasts to laminin (LM)-111 in the presence of transforming growth factor-β induces significant expression of the matrix metalloproteinase (MMP)-3. Here we go on to investigate the regulation of additional MMPs and their specific tissue inhibitors of matrix proteases (TIMPs). Changes in steady-state mRNA levels encoding TIMPs and MMPs were investigated by quantitative reverse transcription–polymerase chain reaction. Production of MMPs was monitored by a multiplexed immunoarray. Signal transduction pathways were studied by immunoblotting. Attachment of synovial fibroblasts to LM-111 in the presence of transforming growth factor-β induced significant increases in MMP-3 mRNA (12.35-fold, p<0.001) and protein (mean 62 ng/ml, sixfold, p<0.008) and in expression of MMP-10 mRNA (11.68-fold, p<0.05) and protein (54 ng/ml, 20-fold, p⩾0.02). All other TIMPs and MMPs investigated failed to show this LM-111-facilitated transforming growth factor-β response. No phosphorylation of nuclear factor-κB was observed. We conclude that co-stimulation of synovial fibroblasts by LM-111 together with transforming growth factor-β suffices to induce significant expression of MMP-3 and MMP-10 by synovial fibroblasts and that this induction is independent of nuclear factor-κB phosphorylation.

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