scholarly journals The Bromodomain Inhibitor N-Methyl pyrrolidone Prevents Osteoporosis and BMP-Triggered Sclerostin Expression in Osteocytes

2018 ◽  
Vol 19 (11) ◽  
pp. 3332 ◽  
Author(s):  
Barbara Siegenthaler ◽  
Chafik Ghayor ◽  
Bebeka Gjoksi-Cosandey ◽  
Nisarat Ruangsawasdi ◽  
Franz Weber
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Osteoporosis Treatment ◽  
Estrogen Deficiency ◽  
Bone Morphogenetic Protein 2 ◽  
Protein Levels ◽  
Osteoporosis Management ◽  
Promising Target

(1) Background: In an adult skeleton, bone is constantly renewed in a cycle of bone resorption, followed by bone formation. This coupling process, called bone remodeling, adjusts the quality and quantity of bone to the local needs. It is generally accepted that osteoporosis develops when bone resorption surpasses bone formation. Osteoclasts and osteoblasts, bone resorbing and bone forming cells respectively, are the major target in osteoporosis treatment. Inside bone and forming a complex network, the third and most abundant cells, the osteocytes, have long remained a mystery. Osteocytes are responsible for mechano-sensation and -transduction. Increased expression of the osteocyte-derived bone inhibitor sclerostin has been linked to estrogen deficiency-induced osteoporosis and is therefore a promising target for osteoporosis management. (2) Methods: Recently we showed in vitro and in vivo that NMP (N-Methyl-2-pyrrolidone) is a bioactive drug enhancing the BMP-2 (Bone Morphogenetic Protein 2) induced effect on bone formation while blocking bone resorption. Here we tested the effect of NMP on the expression of osteocyte-derived sclerostin. (3) Results: We found that NMP significantly decreased sclerostin mRNA and protein levels. In an animal model of osteoporosis, NMP prevented the estrogen deficiency-induced increased expression of sclerostin. (4) Conclusions: These results support the potential of NMP as a novel therapeutic compound for osteoporosis management, since it preserves bone by a direct interference with osteoblasts and osteoclasts and an indirect one via a decrease in sclerostin expression by osteocytes.

scholarly journals 5-Lipoxygenase Metabolites Inhibit Bone Formation in Vitro

Endocrinology ◽  
1998 ◽  
Vol 139 (7) ◽  
pp. 3178-3184 ◽  
Author(s):  
Kathy Traianedes ◽  
Mark R. Dallas ◽  
I. Ross Garrett ◽  
Gregory R. Mundy ◽  
Lynda F. Bonewald
Keyword(s):  
Arachidonic Acid ◽  
Bone Resorption ◽  
Bone Formation ◽  
Osteoclast Formation ◽  
Bone Morphogenetic Protein 2 ◽  
Inflammatory Conditions ◽  
Fetal Rat ◽  
Human Bone Morphogenetic Protein

Abstract The leukotrienes and peptido-leukotrienes are 5-lipoxygenase (5-LO) metabolites of arachidonic acid that appear to have unique effects on bone, distinct from those of the prostaglandins. Application of exogenous leukotrienes in vitro and in vivo results in increased osteoclast formation and bone resorption. While 5-LO metabolites of arachidonic acid clearly stimulate osteoclastic bone resorption, little is known concerning their effects on osteoblastic bone formation. We examined the effects of the 5-LO metabolites 5-HETE, the leukotriene LTB4 and, as representative of the peptido-leukotrienes, LTD4 on the formation of mineralized nodules of fetal rat calvarial cells in the presence of dexamethasone and recombinant human bone morphogenetic protein-2 (rhBMP-2). We also examined the effects of these 5-LO metabolites on alkaline phosphatase activity and cell proliferation in these cultures and the effects of 5-HETE and LTB4 on cultured explants of neonatal murine calvariae. We found that the bone-forming capacity of osteoblasts was impaired when cells were cultured in the presence of 5-LO metabolites. These data indicate that metabolites of the 5-LO pathway are negative regulators of bone formation. The continued presence of these metabolites in the bone environment might account, in part, for the bone loss associated with chronic inflammatory conditions.

scholarly journals The Bone Regeneration Capacity of BMP-2 + MMP-10 Loaded Scaffolds Depends on the Tissue Status

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 979
Author(s):  
Patricia Garcia-Garcia ◽  
Ricardo Reyes ◽  
José Antonio Rodriguez ◽  
Tomas Martín ◽  
Carmen Evora ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Regeneration ◽  
Growth Promotion ◽  
Tissue Growth ◽  
Bone Morphogenetic Protein 2 ◽  
Morphogenetic Protein ◽  
Therapeutic Molecules ◽  
Positive Effect

Biomaterials-mediated bone formation in osteoporosis (OP) is challenging as it requires tissue growth promotion and adequate mineralization. Based on our previous findings, the development of scaffolds combining bone morphogenetic protein 2 (BMP-2) and matrix metalloproteinase 10 (MMP-10) shows promise for OP management. To test our hypothesis, scaffolds containing BMP-2 + MMP-10 at variable ratios or BMP-2 + Alendronate (ALD) were prepared. Systems were characterized and tested in vitro on healthy and OP mesenchymal stem cells and in vivo bone formation was studied on healthy and OP animals. Therapeutic molecules were efficiently encapsulated into PLGA microspheres and embedded into chitosan foams. The use of PLGA (poly(lactic-co-glycolic acid)) microspheres as therapeutic molecule reservoirs allowed them to achieve an in vitro and in vivo controlled release. A beneficial effect on the alkaline phosphatase activity of non-OP cells was observed for both combinations when compared with BMP-2 alone. This effect was not detected on OP cells where all treatments promoted a similar increase in ALP activity compared with control. The in vivo results indicated a positive effect of the BMP-2 + MMP-10 combination at both of the doses tested on tissue repair for OP mice while it had the opposite effect on non-OP animals. This fact can be explained by the scaffold’s slow-release rate and degradation that could be beneficial for delayed bone regeneration conditions but had the reverse effect on healthy animals. Therefore, the development of adequate scaffolds for bone regeneration requires consideration of the tissue catabolic/anabolic balance to obtain biomaterials with degradation/release behaviors suited for the existing tissue status.

scholarly journals Scl-Ab reverts pro-osteoclastogenic signaling and resorption in estrogen deficient osteocytes

2020 ◽  
Author(s):  
Hollie Allison ◽  
Gill Holdsworth ◽  
Laoise M McNamara
Keyword(s):  
Bone Resorption ◽  
Animal Studies ◽  
Cell Signalling ◽  
Estrogen Deficiency ◽  
Neutralising Antibodies ◽  
Decrease Bone Resorption ◽  
Sclerostin Antibody ◽  
Reduce Fracture Risk

Abstract Background Neutralising antibodies to sclerostin (Scl-Ab) have shown significant potential to induce bone formation and decrease bone resorption, increase strength and substantially reduce fracture risk in animal studies and clinical trials. Mechanical loading negatively regulates sclerostin expression, and sclerostin has been shown to induce RANKL synthesis in osteocytes. We have recently discovered that osteoblasts and osteocytes alter osteoclastogenic signalling (RANKL/OPG) during estrogen-deficiency, and that osteoblast-induced osteoclastogenesis and resorption are exacerbated. However, it is not known whether estrogen deficient osteocytes exhibit exacerbate osteoclastogenesis. The aims of this study were to (1) establish whether osteocytes induce osteoclastogenesis and bone resorption during estrogen deficiency in vitro (2) investigate whether the sclerostin antibody can revert osteocyte-mediated osteoclastogenesis and resorption by attenuating RANKL/OPG production. Results Using conditioned media and co-culture experiments we found increased osteocyte-induced osteoclastogenesis and bone resorption in estrogen deficient conditions. This is the first study to report that administration of Scl-Ab decreased RANKL/OPG ratio and increased WISP1 expression in osteocytes and reduced osteoclastogenesis and bone resorption in vitro. Conclusions This study provides an enhanced understanding of the biological changes underpinning decreases in bone resorption following Scl-Ab treatment observed in vivo by revealing that Scl-Ab can reduce pro-osteoclastogenic cell signalling between osteocytes and osteoclasts.

scholarly journals Scl-Ab reverts pro-osteoclastogenic signalling and resorption in estrogen deficient osteocytes 

2020 ◽  
Author(s):  
Hollie Allison ◽  
Gill Holdsworth ◽  
Laoise M McNamara
Keyword(s):  
Bone Resorption ◽  
Animal Studies ◽  
Cell Signalling ◽  
Osteoclast Differentiation ◽  
Estrogen Deficiency ◽  
Decrease Bone Resorption ◽  
And Function ◽  
Sclerostin Antibody

Abstract Neutralising antibodies to sclerostin (Scl-Ab) have shown significant potential to induce bone formation and decrease bone resorption, increase strength and substantially reduce fracture risk in animal studies and clinical trials. Mechanical loading negatively regulates sclerostin expression, and sclerostin has been shown to induce RANKL synthesis in osteocytes. However, how Scl-Ab governs osteocyte regulation of osteoclast differentiation and function is not fully understood. We have recently discovered that osteoblasts and osteocytes alter osteoclastogenic signalling (RANKL/OPG) during estrogen-deficiency, and that osteoblast-induced osteoclastogenesis and resorption are exacerbated. However, it is not known whether estrogen deficient osteocytes exhibit exacerbate osteoclastogenesis. The aims of this study were to (1) establish whether osteocytes induce osteoclastogenesis and bone resorption during estrogen deficiency in vitro (2) investigate whether the sclerostin antibody can revert osteocyte-mediated osteoclastogenesis and resorption by attenuating RANKL/OPG expression.Results Using conditioned media and co-culture experiments we found increased osteocyte-induced osteoclastogenesis and bone resorption in estrogen deficient conditions. This is the first study to report that administration of Scl-Ab has the ability to revert osteocyte-mediated osteoclastogenesis and resorption by decreasing RANKL/OPG ratio expression and increasing WISP1 expression in estrogen deficient osteocytes. ConclusionsThis study provides an enhanced understanding of the biological changes underpinning decreases in bone resorption following Scl-Ab treatment observed in vivo by revealing that Scl-Ab can reduce pro-osteoclastogenic cell signalling between osteocytes and osteoclasts.

scholarly journals Biomimetic coatings for bone tissue engineering of critical-sized defects

2010 ◽  
Vol 7 (suppl_5) ◽  
Author(s):  
Yuelian Liu ◽  
Gang Wu ◽  
Klaas de Groot
Keyword(s):  
Tissue Engineering ◽  
Bone Formation ◽  
Bone Tissue Engineering ◽  
Bone Tissue ◽  
Maxillofacial Surgery ◽  
Bone Morphogenetic Protein 2 ◽  
Native Bone ◽  
Biomimetic Coating

The repair of critical-sized bone defects is still challenging in the fields of implantology, maxillofacial surgery and orthopaedics. Current therapies such as autografts and allografts are associated with various limitations. Cytokine-based bone tissue engineering has been attracting increasing attention. Bone-inducing agents have been locally injected to stimulate the native bone-formation activity, but without much success. The reason is that these drugs must be delivered slowly and at a low concentration to be effective. This then mimics the natural method of cytokine release. For this purpose, a suitable vehicle was developed, the so-called biomimetic coating, which can be deposited on metal implants as well as on biomaterials. Materials that are currently used to fill bony defects cannot by themselves trigger bone formation. Therefore, biological functionalization of such materials by the biomimetic method resulted in a novel biomimetic coating onto different biomaterials. Bone morphogenetic protein 2 (BMP-2)-incorporated biomimetic coating can be a solution for a large bone defect repair in the fields of dental implantology, maxillofacial surgery and orthopaedics. Here, we review the performance of the biomimetic coating both in vitro and in vivo .

scholarly journals Magnesium hydroxide-incorporated PLGA composite attenuates inflammation and promotes BMP2-induced bone formation in spinal fusion

2020 ◽  
Vol 11 ◽  
pp. 204173142096759
Author(s):  
Tarek M. Bedair ◽  
Chang Kyu Lee ◽  
Da-Seul Kim ◽  
Seung-Woon Baek ◽  
Hanan M. Bedair ◽  
...  
Keyword(s):  
Bone Formation ◽  
Spinal Fusion ◽  
Magnesium Hydroxide ◽  
Inflammatory Responses ◽  
Composite Scaffold ◽  
Bone Morphogenetic Protein 2 ◽  
In Vitro Test ◽  
Fusion Model

Spinal fusion has become a common surgical technique to join two or more vertebrae to stabilize a damaged spine; however, the rate of pseudarthrosis (failure of fusion) is still high. To minimize pseudarthrosis, bone morphogenetic protein-2 (BMP2) has been approved for use in humans. In this study, we developed a poly(lactide-co-glycolide) (PLGA) composite incorporated with magnesium hydroxide (MH) nanoparticles for the delivery of BMP2. This study aimed to evaluate the effects of released BMP2 from BMP2-immobilized PLGA/MH composite scaffold in an in vitro test and an in vivo mice spinal fusion model. The PLGA/MH composite films were fabricated via solvent casting technique. The surface of the PLGA/MH composite scaffold was modified with polydopamine (PDA) to effectively immobilize BMP2 on the PLGA/MH composite scaffold. Analyzes of the scaffold revealed that using PLGA/MH-PDA improved hydrophilicity, degradation performance, neutralization effects, and increased BMP2 loading efficiency. In addition, releasing BMP2 from the PLGA/MH scaffold significantly promoted the proliferation and osteogenic differentiation of MC3T3-E1 cells. Furthermore, the pH neutralization effect significantly increased in MC3T3-E1 cells cultured on the BMP2-immobilized PLGA/MH scaffold. In our animal study, the PLGA/MH scaffold as a BMP2 carrier attenuates inflammatory responses and promotes BMP2-induced bone formation in posterolateral spinal fusion model. These results collectively demonstrate that the BMP2-immobilized PLGA/MH scaffold offers great potential in effectively inducing bone formation in spinal fusion surgery.

scholarly journals Evaluation of a Thiolated Chitosan Scaffold for Local Delivery of BMP-2 for Osteogenic Differentiation and Ectopic Bone Formation

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
In-Ho Bae ◽  
Byung-Chul Jeong ◽  
Min-Suk Kook ◽  
Sun-Hun Kim ◽  
Jeong-Tae Koh
Keyword(s):  
Bone Formation ◽  
Release Kinetics ◽  
Ectopic Bone Formation ◽  
Bone Morphogenetic Protein 2 ◽  
Osteoblastic Cell ◽  
Mineral Density ◽  
Thiolated Chitosan ◽  
Ectopic Bone

Thiolated chitosan (Thio-CS) is a well-established pharmaceutical excipient for drug delivery. However, its use as a scaffold for bone formation has not been investigated. The aim of this study was to evaluate the potential of Thio-CS in bone morphogenetic protein-2 (BMP-2) delivery and bone formation.In vitrostudy showed that BMP-2 interacted with the Thio-CS and did not affect the swelling behavior. The release kinetics of BMP-2 from the Thio-CS was slightly delayed (70%) within 7 days compared with that from collagen gel (Col-gel, 85%), which is widely used in BMP-2 delivery. The BMP-2 released from Thio-CS increased osteoblastic cell differentiation but did not show any cytotoxicity until 21 days. Analysis of thein vivoectopic bone formation at 4 weeks of posttransplantation showed that use of Thio-CS for BMP-2 delivery induced more bone formation to a greater extent (1.8 fold) than that of Col-gel. However, bone mineral density in both bones was equivalent, regardless of Thio-CS or Col-gel carrier. Taken together, Thio-CS system might be useful for delivering osteogenic protein BMP-2 and present a promising bone regeneration strategy.

scholarly journals The Importance of the Prenyl Group in the Activities of Osthole in Enhancing Bone Formation and Inhibiting Bone ResorptionIn Vitro

2014 ◽  
Vol 2014 ◽  
pp. 1-16 ◽  
Author(s):  
Yuan-Kun Zhai ◽  
Ya-Lei Pan ◽  
Yin-Bo Niu ◽  
Chen-Rui Li ◽  
Xiang-Long Wu ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Phosphatase Activity ◽  
Osteoporosis Treatment ◽  
Bone Morphogenetic Protein 2 ◽  
Tartrate Resistant Acid Phosphatase ◽  
Protective Effects ◽  
Morphogenetic Protein ◽  
Enhanced Secretion ◽  
Related Transcription Factor

Osteoporosis treatment always aimed at keeping the balance of bone formation and bone resorption. Recently, prenyl group in natural products has been proposed as an active group to enhance the osteogenesis process. Osthole has both the prenyl group and bone-protective activities, but the relationship is still unknown. In this study we found that osthole exerted a potent ability to promote proliferation and osteogenic function of rat bone marrow stromal cells and osteoblasts, including improved cell viability, alkaline phosphatase activity, enhanced secretion of collagen-I, bone morphogenetic protein-2, osteocalcin and osteopontin, stimulated mRNA expression of insulin-like growth factor-1, runt-related transcription factor-2, osterix, OPG (osteoprotegerin), RANKL (receptor activator for nuclear factor-κB ligand), and the ratio of OPG/RANKL, as well as increasing the formation of mineralized nodules. However, 7-methoxycoumarin had no obvious effects. Osthole also inhibited osteoclastic bone resorption to a greater extent than 7-methoxycoumarin, as shown by a lower tartrate-resistant acid phosphatase activity and lower number and smaller area of resorption pits. Our findings demonstrate that osthole could be a potential agent to stimulate bone formation and inhibit bone resorption, and the prenyl group plays an important role in these bone-protective effects.

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