The p38α MAPK is required for regulating osteoblast function and bone formation

Bone ◽  
2011 ◽  
Vol 48 ◽  
pp. S65
Author(s):  
C. Thouverey⁎ ◽  
J. Caverzasio
Keyword(s):  
Bone Formation ◽  
Osteoblast Function ◽  
P38α Mapk

High Serum Sclerostin Correlates with Advanced Stage, Increased Bone Resorption, Reduced Osteoblast Function, and Poor Survival in Newly-Diagnosed Patients with Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 425-425 ◽  
Author(s):  
Evangelos Terpos ◽  
Dimitrios Christoulas ◽  
Eirini Katodritou ◽  
Cornelia Bratengeier ◽  
Brigitte Lindner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Detection Limit ◽  
Bone Resorption ◽  
Bone Formation ◽  
Median Survival ◽  
Healthy Controls ◽  
Poor Survival ◽  
Myeloma Cells ◽  
Osteoblast Function ◽  
Standard Range

Abstract Abstract 425 Multiple myeloma (MM) is characterized by the presence of lytic bone disease due to increased osteoclast activity which is accompanied by reduced osteoblast function. To-date dickkopf-1 (Dkk-1) is considered as the main osteoblast inhibitor which is overproduced by myeloma cells and inhibits Wnt signaling leading to osteoblast exhaustion. Sclerostin is another canonical Wnt antagonist through its binding to low-density lipoprotein-receptor-related protein 5/6. Sclerostin is specifically expressed by osteocytes and inhibits bone morphogenic protein-induced osteoblast differentiation and ectopic bone formation. Osteonectin (SPARC) is a multi-faceted protein that belongs to a family of matricellular proteins. It is secreted by osteoblasts during bone formation, initiating mineralization and promoting mineral crystal formation. SPARC shows affinity for collagen in addition to bone mineral calcium. The aim of this study contacted by the Greek Myeloma Study Group in collaboration with Biomarker Design Forschungs GmbH (BDF), Vienna, Austria was to evaluate, for the first time in the literature, the serum levels of sclerostin in patients with MM and explore possible correlations with clinical and laboratory data, including SPARC levels, ISS stage and survival. One hundred and fifty-seven patients (87M/70F, median age 68 years) with MM at diagnosis before the administration of any type of therapy, including bisphosphonates, were evaluated. Serum sclerostin and SPARC were measured using an ELISA methodology developed by BDF for Biomedica Medizinprodukte GmbH & Co KG (Vienna, Austria). Both assays are sandwich type ELISA using biotinylated antibodies/HRP-streptavidine for the detection of sclerostin and SPARC in the serum. The detection limit of the sclerostin ELISA was 0.18 ng/ml and the coefficient of variation (CV) 6%. The standard range was set from 0.3-3 ng/ml. For the SPARC ELISA we found a detection limit of 1.95 ng/ml and CVs of 8% using a standard range from 5-130 ng/ml. Serum sclerostin and SPARC were determined in MM patients, 21 patients with MGUS and 21 healthy controls, of similar gender and age. Bone remodeling was also studied by the measurement of a series of serum indices within one week from diagnosis: i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)], ii) Dkk-1, iii) bone resorption markers [C-terminal cross-linking telopeptide of collagen type-I (CTX) and 5b-isoenzyme of tartrate resistant acid phosphatase (TRACP-5b)], and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Patients with MM had increased levels of serum sclerostin compared with MGUS patients (mean value±SD: 0.48±0.46 vs. 0.26±0.29 ng/ml; p=0.004) and healthy controls (0.31±0.20 ng/ml, p=0.01). In contrast, both patients with MM and MGUS had reduced levels of serum SPARC (26.3±16.2 and 27.2±18.0 ng/ml, respectively) compared to controls (52.8±50.2 ng/ml; p<0.001). Sclerostin values strongly correlated with beta2-microglobulin (r=0.354, p<0.0001), cystatin-C (r=0.389, p<0.0001), serum creatinine (r=0.380, p<0.0001), and bALP (r=-0.541, p<0.0001). No correlations were observed between sclerostin with sRANKL, OPG, Dkk-1 or SPARC. Patients with advanced bone disease assessed by conventional radiography (>3 lytic lesions and/or a pathological fracture) had a borderline increase of sclerostin compared to all others (median value: 0.51 vs. 0.41 ng/ml, p=0.09). Patients with ISS-3 disease had increased levels of sclerostin compared to patients with ISS-1 and ISS-2 MM (ANOVA p=0.001). Median survival of MM patients was 48 months and median follow-up period was 20 months. Patients who had a serum sclerostin of ≥0.62 ng/ml (upper quartile, n=40 patients) had a median survival of 27 months, while median survival of all other patients was 98 months (p=0.031). In conclusion, our study provided evidence that sclerostin is increased in the serum of patients with MM and correlates with advanced ISS stage, increased bone resorption, reduced osteoblast function and poor survival. SPARC is reduced in MM possibly confirming the reduced osteoblast function observed in these patients. Sclerostin seems to participate in the biology of MM and thus it may be a possible target for the development of novel therapies that can both increase osteoblast function and target myeloma cells. Disclosures: No relevant conflicts of interest to declare.

Distinct Gene Expression Patterns Defining Human Osteoblasts' Response to BMP2 Treatment: Is the Therapeutic Success All a Matter of Timing?

2016 ◽  
Vol 57 (3-4) ◽  
pp. 197-210 ◽  
Author(s):  
Sabrina Ehnert ◽  
Romina Haydée Aspera-Werz ◽  
Thomas Freude ◽  
Marie Karolina Reumann ◽  
Björn Gunnar Ochs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Therapeutic Success ◽  
Human Osteoblasts ◽  
Osteoblast Function ◽  
Repulsive Guidance Molecule

Background: Bone morphogenetic proteins (BMPs) play a key role in bone formation. Local application of BMP2 (Dibotermin alfa) supports bone formation when applied to complex fractures. However, up to 33% of patients do not respond to this therapy. Purpose: Aiming to investigate whether inter-individual responses to BMP2 treatment can be predicted by gene expression patterns, we investigated the effect of BMP2 on primary human osteoblasts and THP-1 cell-derived osteoclasts from 110 donors. Methods: Osteoblasts were obtained by collagenase digestion of spongy bone tissues. Osteoclasts were differentiated from THP-1 cells using the conditioned media of the osteoblasts. Viability was determined by resazurin conversion. As functional characteristics AP and Trap5B activity were measured. Gene expression levels were determined by RT-PCR in 21 of the 110 evaluated donors and visualized by electrophoresis. Results: Based on our data, we could classify three response groups: (i) In 51.8% of all donors, BMP2 treatment induced osteoblast function. These donors strongly expressed the BMP2 inhibitor Noggin (NOG), the alternative BMP2 receptors repulsive guidance molecule B (RGMb) and activin receptor-like kinase 6 (Alk6), as well as the Wnt inhibitor sclerostin (SOST). (ii) In 17.3% of all donors, BMP2 treatment induced viability. In these donors, the initial high SOST expression significantly dropped with BMP2 treatment. (iii) 30.9% of all donors were not directly affected by BMP2 treatment. These donors expressed high levels of the pseudoreceptor BMP and activin membrane-bound inhibitor (BAMBI) and lacked SOST expression. In all donors, SOST expression correlated directly with receptor activator of NF-κB ligand (RANKL) expression, defining the cells' potential to stimulate osteoclastogenesis. Conclusions: Our data identified three donor groups profiting from BMP2 treatment either directly via stimulation of osteoblast function or viability and/or indirectly via inhibition of osteoclastogenesis, depending on their expression of BAMBI, SOST, NOG, and RANKL. On the basis of patients' respective expression profiles, the clinical application of BMP2 as well as its timing might be modified in order to better fit the patients' needs to promote bone formation or to inhibit bone resorption.

scholarly journals Identification of Novel Biphenyl Carboxylic Acid Derivatives as Novel Antiresorptive Agents that Do Not Impair Parathyroid Hormone-Induced Bone Formation

Endocrinology ◽  
2008 ◽  
Vol 150 (1) ◽  
pp. 5-13 ◽  
Author(s):  
Aymen I. Idris ◽  
Iain R. Greig ◽  
Euphemie Bassonga-Landao ◽  
Stuart H. Ralston ◽  
Rob J. van 't Hof
Keyword(s):  
Carboxylic Acid ◽  
Bone Formation ◽  
Nuclear Factor Κb ◽  
Osteoclast Formation ◽  
Nuclear Factor ◽  
Inhibitory Effects ◽  
Osteoblast Function ◽  
Ovariectomized Mice

Bisphosphonates are widely used in the treatment of osteoporosis, but they inhibit bone formation and blunt the anabolic effect of PTH. Here we describe a novel series of compounds that have potent antiresorptive effects in vitro and in vivo that do not adversely affect osteoblast function. The effects of the compounds on osteoclast formation and survival were studied on mouse osteoclasts generated from bone marrow macrophages and on osteoblast function using primary mouse calvarial osteoblast cultures and bone nodule cultures. Studies were performed in vivo using sham-operated or ovariectomized mice. The most potent compound tested was ABD350, a halogen-substituted derivative of the parent compound ABD56 in which the labile ester bond was replaced by a reduced ketone link, with IC50 osteoclast formation at a concentration of 1.3 μm. All compounds inhibited receptor activator of nuclear factor-κB ligand-induced inhibitor of nuclear factor κB phosphorylation and caused osteoclast apoptosis but no inhibitory effects on osteoblast function were observed at concentrations of up to 20μm. ABD350 prevented ovariectomy-induced bone loss when given ip (5 mg/kg · d), whereas ABD56 was only partially effective at this dose. In contrast to the bisphosphonate alendronate, ABD350 had no inhibitory effect on PTH-induced bone formation in ovariectomized mice. In conclusion, the biphenyl carboxylic acid derivatives like ABD350 represent a new class of antiresorptive drugs that inhibit osteoclast activity but have no significant inhibitory effects on osteoblast activity in vitro or PTH-induced bone formation in vivo. The biphenyl-carboxylate ABD350 inhibits osteoclast formation in vitro and in vivo and, unlike the bisphosphonate Alendronate, does not inhibit the bone anabolic effects of PTH.

scholarly journals Osteopotentia regulates osteoblast maturation, bone formation, and skeletal integrity in mice

2010 ◽  
Vol 189 (3) ◽  
pp. 511-525 ◽  
Author(s):  
Michael L. Sohaskey ◽  
Yebin Jiang ◽  
Jenny J. Zhao ◽  
Andreas Mohr ◽  
Frank Roemer ◽  
...  
Keyword(s):  
Bone Formation ◽  
Matrix Protein ◽  
Molecular Mechanisms ◽  
Type I Collagen ◽  
Skeletal Development ◽  
Control Point ◽  
Type I ◽  
Osteoblast Function ◽  
Skeletal Defects ◽  
Osteoblast Maturation

During skeletal development and regeneration, bone-forming osteoblasts respond to high metabolic demand by active expansion of their rough endoplasmic reticulum (rER) and increased synthesis of type I collagen, the predominant bone matrix protein. However, the molecular mechanisms that orchestrate this response are not well understood. We show that insertional mutagenesis of the previously uncharacterized osteopotentia (Opt) gene disrupts osteoblast function and causes catastrophic defects in postnatal skeletal development. Opt encodes a widely expressed rER-localized integral membrane protein containing a conserved SUN (Sad1/Unc-84 homology) domain. Mice lacking Opt develop acute onset skeletal defects that include impaired bone formation and spontaneous fractures. These defects result in part from a cell-autonomous failure of osteoblast maturation and a posttranscriptional decline in type I collagen synthesis, which is concordant with minimal rER expansion. By identifying Opt as a crucial regulator of bone formation in the mouse, our results uncover a novel rER-mediated control point in osteoblast function and implicate human Opt as a candidate gene for brittle bone disorders.

scholarly journals Protein Kinase G Activation Reverses Oxidative Stress and Restores Osteoblast Function and Bone Formation in Male Mice With Type 1 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (4) ◽  
pp. 607-623 ◽  
Author(s):  
Hema Kalyanaraman ◽  
Gerburg Schwaerzer ◽  
Ghania Ramdani ◽  
Francine Castillo ◽  
Brian T. Scott ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 1 Diabetes ◽  
Protein Kinase ◽  
Bone Formation ◽  
Protein Kinase G ◽  
Male Mice ◽  
Osteoblast Function

The Inhibition of the Osteoblast Niche during Hematopoietic Stem Cell Mobilization Is an Indirect Effect Involving Mature Bone Marrow Leukocytes, IL6 and Soluble IL6 Receptor.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1966-1966 ◽  
Author(s):  
Jean-Pierre Levesque ◽  
Ingrid G. Winkler ◽  
Natalie Sims ◽  
Howard Morris ◽  
Paul J. Simmons ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Indirect Effect ◽  
Mrna Levels ◽  
Adhesive Interaction ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Kit Ligand ◽  
Osteoblast Function ◽  
Osteocalcin Production

Abstract Mobilization of hematopoietic stem cells (HSC) involves the disruption of 1) the adhesive interaction between VCAM-1 and α4-integrins and 2) the chemotactic interaction between CXCL12 and CXCR4, interactions which are both required for the retention of HSC within the bone marrow (BM). Experiments in mice deficient in neutrophil proteases have shown that while the disruption of the VCAM-1/α4 integrin interaction is entirely due to the proteolytic cleavage of VCAM-1 by proteases released from neutrophils accumulating in mobilized BM, the down-regulation of CXCL12 involves protease-independent mechanisms. We have recently shown that osteoblasts are the main source of CXCL12 in the BM and that both the number of osteoblasts lining the endosteum and bone formation are dramatically reduced during G-CSF administration as reflected by bone pain often experienced by mobilized donors. Consequently, the decreased level of CXCL12 levels in mobilized BM could be due to inhibition of osteoblasts, an essential component of the hematopoietic niche. Quantitative real-time RT-PCR were performed on mouse BM cells to follow osteocalcin mRNA levels. Osteocalcin mRNA dropped 2–3 logs during mobilization induced by either G-CSF or cyclophosphamide showing that the inhibition of osteoblast function is not restricted to G-CSF-induced mobilization. Morphometric analyses of tibia sections showed a quasi disappearance of osteoblasts and osteoid as early as day 2 of G-CSF injection. In humans, we observed a significant reduction of osteocalcin protein concentration in the plasma during mobilization induced by either G-CSF alone, G-CSF+ KIT ligand or IL3+GM-CSF, showing that in both humans and mice this effect is not restricted to G-CSF. In cultures of purified human osteoblasts, neither G-CSF, KIT ligand, IL3 nor GM-CSF inhibited osteocalcin production demonstrating that inhibition of osteoblast function is not a direct effect of these cytokines. In parallel experiments, addition of differentiated BM CD34− leukocytes to osteoblast cultures, resulted in a dose-dependant inhibition of osteocalcin production showing that the effect is mediated by mature leukocytes. Since IL6 and soluble IL6 receptor (sIL6R) are important mediators of bone formation, we tested these two cytokines on purified osteoblasts and found that the combination of IL6+sIL6R was a potent inhibitor of osteocalcin production while these cytokines had no effect when used alone. Furthermore, we find cocultures of osteoblasts and BM leukocytes results in a 30-fold increase in IL6 production compared to monocultures of osteoblasts or BM leukocytes. Finally, in humans, plasma concentration of sIL6R is significantly increased during HSC mobilization and this increase is significantly correlated with the number of circulating CFU-GM. Taken together, these data indicate that the inhibition of osteoblast function during HSC mobilization is an indirect effect involving mature BM leukocytes, IL6 and sIL6R.

miR ‐433‐3p Suppresses Bone Formation and mRNAs Critical for Osteoblast Function in Mice

2021 ◽  
Author(s):  
John Garcia ◽  
Spenser S. Smith ◽  
Sangita Karki ◽  
Hicham Drissi ◽  
Henry H. Hrdlicka ◽  
...  
Keyword(s):  
Bone Formation ◽  
Osteoblast Function
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