Osteoclast-secreted Cthrc1 in the coupling of bone resorption to formation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE45656 | GEO | 2015/04/01
SECONDARY ACCESSION(S): PRJNA195563
REPOSITORIES: GEO
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Project description:Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts, and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule is the enigmatic coupling factor. We have identified Cthrc1, a protein secreted by mature bone-resorbing osteoclasts, that targets stromal cells so as to stimulate osteogenesis. The expression of Cthrc1 is robustly induced when mature osteoclasts are placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increases in a high turnover state, such as that which is induced by RANKL injections in vivo, whereas it decreases with aging or following alendronate treatment, conditions associated with suppressed bone turnover. The targeted deletion of the Cthrc1 gene eliminates Cthrc1 expression in bone, whereas its deficiency in osteoblasts does not exert any significant effect. Osteoclast-specific deletion of the Cthrc1 gene results in osteopenia due to reduced bone formation: it also impairs the coupling process following resorption induced by RANKL injections, with a resultant impairment of bone mass recovery. Thus, Cthrc1 is an osteoclast-secreted “coupling factor” that regulates bone remodeling and hence, skeletal integrity. Total bone marrow cells were prepared from the femurs and tibias of 8-10-week-old C57BL/6 mice and cultured in the presence of M-CSF (100ng/ml) for 3 days as described previously (Takeshita et al., 2000 JBMR 15:1477-1488). Cells were harvested with 0.02% EDTA/PBS and used as bone marrow macrophages (BMMs). These BMMs were cultured in the presence of M-CSF (100 ng/ml) and RANKL (100ng/ml) for 2 days. TRAP positive mononuclear cells were harvested and used as pre-osteoclasts (pOC). These pOC cells were further cultured in the presence of M-CSF and RANKL for 2 days in normal plastic plate or on dentin slices. After 2 days, multinucleated TRAP positive mature osteoclasts were generated as mature osteoclasts on plate (mOCp) and mature resorbing osteoclasts on dentin (mOCd), respectively. RNAs were extracted from four different stages of osteoclast lineage cells; BMMs, pOC, mOCp and mOCd, and used for microarray analysis.
2015-04-01 | E-GEOD-45656 | biostudies-arrayexpress
Project description:This a model from the article:
Mathematical model of paracrine interactions between osteoclasts and osteoblasts predicts anabolic action of parathyroid hormone on bone.
Komarova SV.
Endocrinology.2005 Aug;146(8):3589-95.
15860557,
Abstract:
To restore falling plasma calcium levels, PTH promotes calcium liberation from bone. PTH targets bone-forming cells, osteoblasts, to increase expression of the cytokine receptor activator of nuclear factor kappaB ligand (RANKL), which then stimulates osteoclastic bone resorption. Intriguingly, whereas continuous administration of PTH decreases bone mass, intermittent PTH has an anabolic effect on bone, which was proposed to arise from direct effects of PTH on osteoblastic bone formation. However, antiresorptive therapies impair the ability of PTH to increase bone mass, indicating a complex role for osteoclasts in the process. We developed a mathematical model that describes the actions of PTH at a single site of bone remodeling, where osteoclasts and osteoblasts are regulated by local autocrine and paracrine factors. It was assumed that PTH acts only to increase the production of RANKL by osteoblasts. As a result, PTH stimulated osteoclasts upon application, followed by compensatory osteoblast activation due to the coupling of osteoblasts to osteoclasts through local paracrine factors. Continuous PTH administration resulted in net bone loss, because bone resorption preceded bone formation at all times. In contrast, over a wide range of model parameters, short application of PTH resulted in a net increase in bone mass, because osteoclasts were rapidly removed upon PTH withdrawal, enabling osteoblasts to rebuild the bone. In excellent agreement with experimental findings, increase in the rate of osteoclast death abolished the anabolic effect of PTH on bone. This study presents an original concept for the regulation of bone remodeling by PTH, currently the only approved anabolic treatment for osteoporosis.
The model reproduces Figures 1B and 2A of the reference publication. To obtain the figures 1B, the parameter g21 needs changes. To obtain the figures 1A, the parameters g21, g12 and k2 need to changed. For details look at the curation tab.
The initial concentration of Osteoclasts (x1) is corrected to 1.06066 from 10.06066.
This model was taken from the
CellML repository and automatically converted to SBML.
The original model was:
CellMLdetails
The original CellML model was created by:
Lloyd, Catherine, May
c.lloyd@auckland.ac.nz
The University of Auckland
The Bioengineering Institute
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
For more information see the terms of use.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2024-09-02 | BIOMD0000000279 | BioModels
Project description:This a model from the article:
Modeling the interactions between osteoblast and osteoclast activities in bone remodeling.
Lemaire V, Tobin FL, Greller LD, Cho CR, Suva LJ.
J Theor Biol.2004 Aug 7;229(3):293-309.
15234198,
Abstract:
We propose a mathematical model explaining the interactions between osteoblasts and osteoclasts, two cell types specialized in the maintenance of the bone integrity. Bone is a dynamic, living tissue whose structure and shape continuously evolves during life. It has the ability to change architecture by removal of old bone and replacement with newly formed bone in a localized process called remodeling. The model described here is based on the idea that the relative proportions of immature and mature osteoblasts control the degree of osteoclastic activity. In addition, osteoclasts control osteoblasts differentially depending on their stage of differentiation. Despite the tremendous complexity of the bone regulatory system and its fragmentary understanding, we obtain surprisingly good correlations between the model simulations and the experimental observations extracted from the literature. The model results corroborate all behaviors of the bone remodeling system that we have simulated, including the tight coupling between osteoblasts and osteoclasts, the catabolic effect induced by continuous administration of PTH, the catabolic action of RANKL, as well as its reversal by soluble antagonist OPG. The model is also able to simulate metabolic bone diseases such as estrogen deficiency, vitamin D deficiency, senescence and glucocorticoid excess. Conversely, possible routes for therapeutic interventions are tested and evaluated. Our model confirms that anti-resorptive therapies are unable to partially restore bone loss, whereas bone formation therapies yield better results. The model enables us to determine and evaluate potential therapies based on their efficacy. In particular, the model predicts that combinations of anti-resorptive and anabolic therapies provide significant benefits compared with monotherapy, especially for certain type of skeletal disease. Finally, the model clearly indicates that increasing the size of the pool of preosteoblasts is an essential ingredient for the therapeutic manipulation of bone formation. This model was conceived as the first step in a bone turnover modeling platform. These initial modeling results are extremely encouraging and lead us to proceed with additional explorations into bone turnover and skeletal remodeling.
This model corresponds to the core model published in the paper. There is no corresponding plot to reproduce for this model.
To obtain each of the 9 plots in the Figure 2 of the reference publication, there are some changes to be made to the core model.
The curation figure reproduces figure 2 of the reference publication. There is a corresponding SBML and Copasi files for each of the plot. See curation tab for more details.
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2010 The BioModels.net Team.
For more information see the terms of use.
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2024-09-02 | BIOMD0000000278 | BioModels
Project description:Purpose: Identification of osteoclast derived coupling factors using Denosumab as a biological probe Method: harvested RNA from centrifuged bone biopsies (heterogeneous population containing bone lining cells, osteoblasts, osteoclasts and osteocytes, without in vitro culture Results: Identification of genes differentially regulated in denosumab treated participants that correlate with bone remodeling indices Conclusions: Using this approach we identified denosumab regulated genes that correlate with bone remodeling in the untreated participants and may represent novel osteoclast derived coupling factors. Of interest, we identified DPP4 to be suppressed in denosumab treated participants, providing a novel link between bone remodeling and energy metabolism.
2019-12-07 | GSE141610 | GEO
Project description:Purpose: Identification of osteoclast derived coupling factors using Denosumab as a biological probe Method: harvested RNA from centrifuged bone biopsies (heterogeneous population containing bone lining cells, osteoblasts, osteoclasts and osteocytes, without in vitro culture Results: Identification of genes differentially regulated in denosumab treated participants that correlate with bone remodeling indices Conclusions: Using this approach we identified denosumab regulated genes that correlate with bone remodeling in the untreated participants and may represent novel osteoclast derived coupling factors. Of interest, we identified DPP4 to be suppressed in denosumab treated participants, providing a novel link between bone remodeling and energy metabolism.
2019-12-07 | GSE141595 | GEO
Project description:Bone remodeling relies on the precise developmental control of osteoclasts that resorb bone and osteoblasts that lay down fresh bone matrix. The hematopoietically derived osteoclast follow a tigthly controlled genetic program where specific genes are up-regulated to aid bone resorption.Some of them for instance control membrane polarization, others transporters and pumps to move the acid and proteases intot he resorption pit. We used microarrays to detail the global programme of gene expression underlying differentiation of osteoclasts and identified distinct classes of up-regulated genes during this process. RAW cells were selected at different time periods of culture during the osteoclast differentiation process for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain more homogenous temporal resolution of expression profiles by using a cell line RAW 264.7 and including data of control cells that had been cultured for similar time periods without RANKL.
2010-08-24 | E-GEOD-21639 | biostudies-arrayexpress
Project description:Bone remodeling, crucial for skeletal integrity, involves osteoclasts and osteoblasts. Osteoclastogenesis, regulated by NFATc1, is activated by c-Fos and NF-κB signaling in response to RANKL. Excessive RANKL signaling contributes to bone loss pathology. Here we reveal denatonium as an inhibitor of RANKL-induced osteoclast differentiation through the p65 pathway. RNA-seq identified downregulated osteoclast-related genes. Affinity chromatography pinpointed 35 denatonium-interacting proteins, with PRDX1 showing specificity. PRDX1 deficiency led to osteoporosis with increased osteoclast activity and enhanced RANKL-induced osteoclast formation. Denatonium blocked PRDX1 lysosomal degradation, stabilizing PRDX1. Through transcription factor binding site analysis, p65 emerged as a major target suppressed by the denatonium-PRDX1 interaction. Chromatin immunoprecipitation confirmed that the denatonium-PRDX1 complex inhibited p65 enrichment at promoter regions critical for osteoclast differentiation. In an osteoporosis animal model, denatonium treatment restored bone health. This study uncovers denatonium's novel role in bone formation regulation by selectively targeting PRDX1, suggesting its potential in osteoporosis treatment.
2024-06-30 | GSE248993 | GEO
Project description:Bone remodeling, crucial for skeletal integrity, involves osteoclasts and osteoblasts. Osteoclastogenesis, regulated by NFATc1, is activated by c-Fos and NF-κB signaling in response to RANKL. Excessive RANKL signaling contributes to bone loss pathology. Here we reveal denatonium as an inhibitor of RANKL-induced osteoclast differentiation through the p65 pathway. RNA-seq identified downregulated osteoclast-related genes. Affinity chromatography pinpointed 35 denatonium-interacting proteins, with PRDX1 showing specificity. PRDX1 deficiency led to osteoporosis with increased osteoclast activity and enhanced RANKL-induced osteoclast formation. Denatonium blocked PRDX1 lysosomal degradation, stabilizing PRDX1. Through transcription factor binding site analysis, p65 emerged as a major target suppressed by the denatonium-PRDX1 interaction. Chromatin immunoprecipitation confirmed that the denatonium-PRDX1 complex inhibited p65 enrichment at promoter regions critical for osteoclast differentiation. In an osteoporosis animal model, denatonium treatment restored bone health. This study uncovers denatonium's novel role in bone formation regulation by selectively targeting PRDX1, suggesting its potential in osteoporosis treatment.
2024-06-30 | GSE248992 | GEO
Project description:Osteoclast derived from macrophage lineage cells are responsible for bone resorption and important in bone remodeling. Emerging of a new discipline-osteoimmunology highlights the important connection between immunology and bone biology. We had mouse osteoclast's RNA samples analyzed by the consortium’s gene microarray and identified a number of significant changes in expression of genes involved in glycan biosynthesis. Osteoclasts were treated with: control, Rankl (Receptor activator of nuclear factor kappa-B ligand (RANKL), tunicamycin, and both rankl and tunicamycin. RNA preparations from osteoclasts purified from mice: control (1,2,3), Rankl (1,2,3), tunicamycin (1,2,3), and both rankl and tunicamycin (1,2,3) were sent to the Microarray Core (E). The RNA was amplified, labeled, and hybridized to the GLYCOv3 microarrays.
2011-04-29 | E-GEOD-28947 | biostudies-arrayexpress
Project description:B-cell lymphoma 3-encoded protein (Bcl3) is an intimate and context-specific regulator of the NF-kB family of transcription factors, a ubiquitous master regulator involved in many homeostatic and inflammatory processes. NF‑kB signalling determines the fates of bone-forming osteoblasts and bone-resorbing osteoclasts. Herein we show that Bcl3 is a negative regulator of NF‑kB via control of osteoblast and osteoclast function. Mice lacking Bcl3 (Bcl3−/−) have congenitally increased bone density, long bone dwarfism, increased biomechanical strength and altered bone turnover. Bcl3−/− osteoblasts and osteoclasts have accelerated differentiation and increased activity; whereas, rescue overexpression with a Bcl3 mimetic peptide inhibits differentiation. Early-differentiating Bcl3−/− osteoblasts have altered gene transcription favouring bone formation, including perturbation of the RANKL-OPG axis. In a model of osteoarthritic aberrant mineralisation Bcl3−/− mice exhibit decreased pathological osteophyte formation. Cumulatively, these findings identify Bcl3 as a viable target for controlling NF‑kB signalling in the treatment of skeletal pathologies.
2019-01-17 | GSE125153 | GEO