Search

Summary: The occurrence and severity of osteonecrosis in sickle cell anaemia (SCA) vary due to risk factors, including genetic modifiers. Bone morphogenetic proteins (BMPs), particularly BMP6, and the vitamin D receptor (VDR) play key roles in cartilage and bone metabolism, making them potential contributors to orthopaedic outcomes in SCA. Here, we evaluated the association of polymorphisms in BMP6 (rs3812163, rs270393 and rs449853) and VDR (FokI rs2228570 and Cdx2 rs11568820) genes with osteonecrosis risk in a Brazilian SCA cohort. A total of 177 unrelated SCA patients were selected. The AA genotype of BMP6 rs3812163 was independently associated with a lower osteonecrosis risk (p = 0.015; odds ratio (OR): 0.38; 95% confidence interval (CI): 0.18–0.83) and with the long‐term cumulative incidence of osteonecrosis (p = 0.029; hazard ratio: 0.56, 95% CI: 0.34–0.94). The VDR rs2228570 TT genotype was independently associated with a lower osteonecrosis risk (p = 0.039; OR: 0.14; 95% CI: 0.02–0.90). In summary, our results provide evidence that BMP6 rs3812163 and the VDR rs2228570 might be implicated in osteonecrosis pathophysiology in SCA and might help identify individuals at high risk. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR), a prevalent complication of diabetes mellitus affecting a significant portion of the global population, has long been viewed primarily as a microvascular disorder. However, emerging evidence suggests that it should be redefined as a neurovascular disease with multifaceted pathogenesis rooted in oxidative stress and advanced glycation end products. The transforming growth factor-β (TGF-β) signaling family has emerged as a major contributor to DR pathogenesis due to its pivotal role in retinal vascular homeostasis, endothelial cell barrier function, and pericyte differentiation. However, the precise roles of TGF-β signaling in DR remain incompletely understood, with conflicting reports on its impact in different stages of the disease. Additionally, the BMP subfamily within the TGF-β superfamily introduces further complexity, with BMPs exhibiting both pro- and anti-angiogenic properties. Furthermore, TGF-β signaling extends beyond the vascular realm, encompassing immune regulation, neuronal survival, and maintenance. The intricate interactions between TGF-β and reactive oxygen species (ROS), non-coding RNAs, and inflammatory mediators have been implicated in the pathogenesis of DR. This review delves into the complex web of signaling pathways orchestrated by the TGF-β superfamily and their involvement in DR. A comprehensive understanding of these pathways may hold the key to developing targeted therapies to halt or mitigate the progression of DR and its devastating consequences. [ABSTRACT FROM AUTHOR]

Introduction: Osseointegration of hip implants, although a decade-long process, shows striking similarities with the four major phases of endochondral bone repair. In the current study we investigated the spatiotemporal involvement of bone morphogenic proteins (BMPs) and transforming growth factor betas (TGF-βs) throughout the process of bone repair leading to successfully osseointegrated hip implants. Materials and methods: Twenty-four patients that had undergone primary total hip arthroplasty (THA) due to one-sided osteoarthritis (OA) were investigated during a period of 18 years (Y) with repeated measurements of plasma biomarkers as well as clinical and radiological variables. All implants were clinically and radiographically well anchored throughout the follow-up. Eighty-one healthy donors divided in three gender- and age-matched groups and twenty OA patients awaiting THA, served as controls. Plasma was analyzed for BMP-1, -2, -3, -4, -6, -7 -9 and TGF-β1, -β2, -β3 by use of a high-sensitivity and wide dynamic range electrochemiluminescence technique allowing for detection of minor changes. Results: Spatiotemporal changes during the follow-up are presented in the context of the four phases of endochondral bone repair shown in earlier studies and transposed to the current study based on similarities in biomarker responses. Phase 1: Primary proinflammatory phase lasting from surgery until day 7, Phase 2: Chondrogenic phase from day 7 until 18 months postsurgery, Phase 3: Secondary proinflammatory and cartilage remodeling phase lasting from 18 months until 7Y, Phase 4: coupled bone remodeling from 7Y until 18Y postsurgery. BMP-1 increased sharply shortly after surgery and remained significantly above healthy during the chondrocyte recruitment, proliferation, and hypertrophy phases with a subsequent return to control level at 5Y postsurgery. BMP-2 was above healthy controls before surgery and 1 day after surgery before decreasing to control level and remaining there throughout the follow-up. BMP-3 was at control level from presurgery until 6M after surgery when it increased to a peak at 2Y during the cartilage hypertrophy phase followed by a gradual decrease to control level at 10Y during the phase of bone formation. In the following, BMP-3 decreased below controls to a nadir 15Y postsurgery during coupled bone remodeling. BMP-4 was at control level from presurgery until 10Y postsurgery when it increased to a sharp peak at 15Y after surgery followed by a return to the level of healthy at 18Y. BMP-6 did not differ from healthy during the follow-up. BMP-7 was at control level from presurgery until 1Y postsurgery before gradually increasing to a peak at 10Y during the early phase of osteogenesis with a gradual return to control level at 18Y during the phase of coupled bone remodeling. BMP-9 was above OA before surgery followed by a decrease to basal level on day 1 after surgery and a renewed increase to a plateau above controls lasting from 6 W until returning to the level of healthy at 18Y postsurgery, i.e., throughout the phases of cartilage formation, cartilage hypertrophy and remodeling, bone formation and coupled bone remodeling. TGF-β1 was above controls presurgery before decreasing to baseline shortly after surgery followed by a renewed increase at 6 M to a peak at 2Y during cartilage hypertrophy/remodeling followed by a gradual return to baseline at 10Y during early osteoblastogenesis. TGF-β2 was at control level from presurgery until the phase of cartilage remodeling at 5Y when it increased sharply to a peak at 7Y with a gradual return to baseline at 18Y postsurgery. TGF-β3 remained at control level throughout the study. Conclusion: This study shows that the involvement of BMPs and TGF-βs in endochondral bone repair is a process of stepwise recruitment of individual biomarkers characterized by distinct, yet overlaping, spatiotemporal patterns that extend from the early phase of pre-chondrocyte recruitment until the late phase of coupled bone remodeling.

Copyright of Van Tip Dergisi is the property of Yuzuncu Yil University, Faculty of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Calciphylaxis is a rare, yet underdiagnosed condition causing high mortality in patients with severe renal and cardiovascular disease. Since knowledge of the pathophysiology of calciphylaxis is limited, a differential analysis of histological alterations in patient subgroups with various comorbidities might expose different disease phenotypes and allow deeper insights into the pathophysiology of the condition. Histological markers of osteogenesis and calcification were investigated in a group of 18 patients with clinically and histologically verified calciphylaxis, using immunohistochemical staining. Analysis of staining intensity and distribution of marker proteins in histological structures was performed to evaluate distinct patterns between subgroups with different clinical comorbidities in comparison with a control group. In all cases, immunohistochemical staining for bone matrix proteins, bone-morphogenic proteins and matrix-Gla proteins co-localized with subcutaneous vascular and interstitial calcifications. Significant expression of bone-morphogenic protein-7 and active matrix-Gla protein was observed. Mortality was associated with renal comorbidities and increased expression of bone-morphogenic protein-7. However, no distinct histological patterns were found between subgroups with renal disease, warfarin intake or coexisting micro- and macro-angiopathies. The upregulation of osteogenic markers (including bone-morphogenic protein-7) plays a major role in the development of calciphylaxis. Clinical outcome correlates with kidney function and phosphate handling, suggesting different pathophysiological mechanisms. However, biopsy at late-stage disease shows a common histological phenotype, involving enchondral ossification.

Calciphylaxis is a rare, yet underdiagnosed condition causing high mortality in patients with severe renal and cardiovascular disease. Since knowledge of the pathophysiology of calciphylaxis is limited, a differential analysis of histological alterations in patient subgroups with various comorbidities might expose different disease phenotypes and allow deeper insights into the pathophysiology of the condition. Histological markers of osteogenesis and calcification were investigated in a group of 18 patients with clinically and histologically verified calciphylaxis, using immunohistochemical staining. Analysis of staining intensity and distribution of marker proteins in histological structures was performed to evaluate distinct patterns between subgroups with different clinical comorbidities in comparison with a control group. In all cases, immunohistochemical staining for bone matrix proteins, bone-morphogenic proteins and matrixGla proteins co-localized with subcutaneous vascular and interstitial calcifications. Significant expression of bone-morphogenic protein-7 and active matrixGla protein was observed. Mortality was associated with renal comorbidities and increased expression of bone-morphogenic protein-7. However, no distinct histological patterns were found between subgroups with renal disease, warfarin intake or coexisting micro- and macro-angiopathies. The upregulation of osteogenic markers (including bone-morphogenic protein-7) plays a major role in the development of calciphylaxis. Clinical outcome correlates with kidney function and phosphate handling, suggesting different pathophysiological mechanisms. However, biopsy at late-stage disease shows a common histological phenotype, involving enchondral ossification. [ABSTRACT FROM AUTHOR]

We investigated the effects of caffeic acid phenethyl ester (CAPE) and low-dose doxycycline (LDD) on sclerostin and bone morphogenic protein (BMP)-2 expression in experimental periodontitis. We used male rats in groups as follows: control group (C), periodontitis + CAPE group (PC), periodontitis + LDD group (PD), periodontitis + LDD + CAPE group (PCD) and periodontitis group (P). We administered 10 µmol/kg/day CAPE by an intraperitoneal (i.p.) injection and 10 mg/kg/day LDD by oral gavage. Histopathological changes among groups were evaluated and compared. Sclerostin and BMP-2 expression was analyzed using immunohistochemistry. LDD and/or CAPE treatment ameliorated pathology. The highest sclerostin and lowest BMP-2 expressions were found in P group. Group PC exhibited the highest BMP-2 expression scores and the most significant improvement among the treatment groups. The lowest sclerostin expression was observed in the PD group. We found that preventing sclerostin activity may be a useful treatment alternative for bone resorption, especially in cases of periodontitis and peri-implantitis. We found that CAPE and/or LDD may act as anti-sclerostin agents. [ABSTRACT FROM AUTHOR]

The aim of the present study was to establish a modular platform of poly‐L‐lysine‐heparin (PLL‐Hep) polyelectrolyte multilayer (PEM) coatings on titanium surfaces for dual growth factor delivery of recombinant human bone morphogenic protein 2 (rhBMP2) and recombinant human vascular endothelial growth factor 165 (rhVEGF165) in clinically relevant quantities. Release characteristics for both growth factors differed significantly depending on film architecture. rhBMP2 induced activation of alkaline phosphatase in C2C12 cells and proliferation of human mesenchymal stem cells (hMSCs). rhVEGF mediated induction of von Willebrand factor (vWF) in hMSCs and proliferation of human umbilical vein endothelial cells. Osteogenic and angiogenic effects were modified by variation in cross‐linking and architecture of the PEMs. By creating multilayer films with distinct zones, release characteristics and proportion of both growth factor delivery could be tuned and surface‐activity modified to enhance angiogenic or osteogenic function in various ways. In summary, the system provides a modular platform for growth factor delivery that allows for individual composition and accentuation of angiogenic and osteogenic surface properties. [ABSTRACT FROM AUTHOR]

The aim of the present study was to develop a collagen/heparin-based multilayer coating on titanium surfaces for retarded release of recombinant human bone morphogenic protein 2 (rhBMP2) to enhance the osteogenic activity of implant surfaces. Polyelectrolyte multilayer (PEM) coatings were constructed on sandblasted/acid-etched surfaces of titanium discs using heparin and collagen. PEM films of ten double layers were produced and overlayed with 200 µL of a rhBMP2 solution containing 15 µg rhBMP2. Subsequently, cross-linking of heparin molecules was performed using EDC/NHS chemistry to immobilize the incorporated rhBMP2. Release characteristics for 3 weeks, induction of Alkaline Phosphatase (ALP) in C2C12 cells and proliferation of human mesenchymal stem cells (hMSCs) were evaluated to analyze the osteogenic capacity of the surface. The coating incorporated 10.5 µg rhBMP2 on average per disc and did not change the surface morphology. The release profile showed a delivery of 14.5% of the incorporated growth factor during the first 24 h with a decline towards the end of the observation period with a total release of 31.3%. Cross-linking reduced the release with an almost complete suppression at 100% cross-linking. Alkaline Phosphatase was significantly increased on day 1 and day 21, indicating that the growth factor bound in the coating remains active and available after 3 weeks. Proliferation of hMSCs was significantly enhanced by the non-cross-linked PEM coating. Nanocoating using collagen/heparin-based PEMs can incorporate clinically relevant amounts of rhBMP2 on titanium surfaces with a retarded release and a sustained enhancement of osteogenic activity without changing the surface morphology. [ABSTRACT FROM AUTHOR]

Introduction: Recent studies have shown a growing concern regarding the cost-effectiveness and the lack of supporting data for the biologic agents that are being increasingly used in the orthopedic field. Our aim was to conduct a systematic scoping review of recent publications (last five years) on the use of orthobiologics to treat fracture non-union and summarize the latest available data., Patients and Methods: The inclusion criteria for this review were articles published in English, from 2016 to 2022, and focusing on the use of orthobiologics for the surgical treatment of non-union. Searches were conducted in March 2023 using Pubmed/MEDLINE and Embase. Studies on spinal fusion or gene therapy were excluded. Reviews, case reports with five cases or less, conference proceedings, preliminary reports, pediatric or non-human studies were excluded as well., Results: The search found 1807 articles, 15 were eligible after PRISMA checklist and exclusions. The evidence was heterogenous and there was only one level II RCT. Recent data suggests that bone morphogenic protein (BMP-2) products could be effective for septic and aseptic tibial non-unions. However, the evidence was not conclusive regarding BMP-7, plasma rich platelets (PRP), stem cells or demineralized bone matrix (DBM)., Discussion: Every non-union case is different in terms of bone defect, biology, mechanical stability, surgical technique and host factors, which contributes to the conflicting reports on the efficacy of orthobiologics in the literature. We might never see a level 1, high powered and robust study defining the efficacy, safety profile and cost-effectiveness of such products., Level of Evidence: IV., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Tissue engineering aims to reconstruct the natural target tissue by a combination of three key elements stem/progenitor cells (that will create the new tissue), signaling molecules (that instruct the cells to form the desired tissue) scaffold/extracellular matrix (to hold the cells). Regeneration of the periodontal tissues following destructive episodes of various forms of periodontitis is a formidable challenge to periodontologists. Bone morphogenic proteins have been considered as the most potent growth factors that can promote the bone regeneration. This review will emphasize on the unique nature of the tissue engineered bone morphogenic proteins molecules regarding their structure, classification, signaling mechanism, etc. which will further help in understanding their role and potential advances necessary to facilitate the process of regeneration in the field of periodontics. [ABSTRACT FROM AUTHOR]

Background/objectives: Polyethylene terephthalate (PET)-based artificial ligaments are one of the most commonly used grafts in anterior cruciate ligament (ACL) reconstruction surgery. However, the lack of favorable hydrophilicity and cell attachment for PET highly impeded its widespread application in clinical practice. Studies found that surface modification on PET materials could enhance the biocompatibility and bioactivity of PET ligaments. In this study, we immobilized bone morphogenetic protein-2 (BMP-2) on the surface of PET ligaments mediated by polydopamine (PDA) coating and investigated the bioactivation and graft-to-bone healing effect of the modified grafts in vivo and in vitro.Methods: In this study, we prepared the PDA coating and subsequent BMP-2-immobilized PET artificial ligaments. Scanning electron microscopy (SEM) was used to analyze the morphological changes of the modified grafts. In addition, the surface wettability properties of the modified ligaments, amount of immobilized BMP 2, and the release of BMP-2 during a dynamic period up to 28 days were tested. Then, the attachment and proliferation of rat bone mesenchymal stem cells (rBMSCs) on grafts were examined by SEM and Cell Counting Kit-8 (CCK-8) assay, respectively. Alkaline phosphatase (ALP) assay, RT-PCR, and Alizarin Red S staining were performed to test the osteoinduction property. For in vivo experiments, an extra-articular graft-to-bone healing model in rabbits was established. At 8 weeks after surgery, biomechanical tests, micro-CT, and histological staining were performed on harvested samples.Results: A surface morphological analysis verified the success of the PDA coating. The wettability of the PET artificial ligaments was improved, and more than 80% of BMP-2 stably remained on the graft surface for 28 days. The modified grafts could significantly enhance the proliferation, attachment, as well as expression of ALP and osteogenic-related genes, which demonstrated the favorable bioactivity of the grafts immobilized with BMP-2 in vitro. Moreover, the grafts immobilized with BMP-2 at a concentration of 138.4 ± 10.6 ng/cm2 could highly improve the biomechanical properties, bone regeneration, and healing between grafts and host bone after the implantation into the rabbits compared with the PDA-PET group or the PET group.Conclusion: The immobilization of BMP-2 mediated by polydopamine coating on PET artificial ligament surface could enhance the compatibility and bioactivity of the scaffolds and the graft-to-bone healing in vivo.

• ID3 remains a transcription factor that cannot be targeted for the prevention or treatment of cancer metastasis. • Milk thistle flavonolignan silibinin blocks the inducible activation of ID3 in brain endothelial cells. • Silibinin prevents the constitutive, acquired, and adaptive expression of ID3 in lung cancer cells. • Silibinin blocks ID3 transcription through BMP-responsive regulatory elements in ID3 gene enhancers. • Silibinin directly inhibits the kinase activity of the BMP receptors ACVRL1/ALK1 and BMPR2. • Silibinin suppresses ID3 overexpression in vivo at clinically relevant concentrations. ID3 (inhibitor of DNA binding/differentiation-3) is a transcription factor that enables metastasis by promoting stem cell-like properties in endothelial and tumor cells. The milk thistle flavonolignan silibinin is a phytochemical with anti-metastatic potential through largely unknown mechanisms. We have mechanistically investigated the ability of silibinin to inhibit the aberrant activation of ID3 in brain endothelium and non-small cell lung cancer (NSCLC) models. Bioinformatic analyses were performed to investigate the co-expression correlation between ID3 and bone morphogenic protein (BMP) ligands/BMP receptors (BMPRs) genes in NSCLC patient datasets. ID3 expression was assessed by immunoblotting and qRT-PCR. Luciferase reporter assays were used to evaluate the gene sequences targeted by silibinin to regulate ID3 transcription. In silico computational modeling and LanthaScreen TR-FRET kinase assays were used to characterize and validate the BMPR inhibitory activity of silibinin. Tumor tissues from NSCLC xenograft models treated with oral silibinin were used to evaluate the in vivo anti-ID3 effects of silibinin. Analysis of lung cancer patient datasets revealed a top-ranked positive association of ID3 with the BMP9 endothelial receptor ACVRL1/ALK1 and the BMP ligand BMP6. Silibinin treatment blocked the BMP9-induced activation of the ALK1-phospho-SMAD1/5-ID3 axis in brain endothelial cells. Constitutive, acquired, and adaptive expression of ID3 in NSCLC cells were all significantly downregulated in response to silibinin. Silibinin blocked ID3 transcription via BMP-responsive elements in ID3 gene enhancers. Silibinin inhibited the kinase activities of BMPRs in the micromolar range, with the lower IC 50 values occurring against ACVRL1/ALK1 and BMPR2. In an in vivo NSCLC xenograft model, tumoral overexpression of ID3 was completely suppressed by systematically achievable oral doses of silibinin. ID3 is a largely undruggable metastasis-promoting transcription factor. Silibinin is a novel suppressor of ID3 that may be explored as a novel therapeutic approach to interfere with the metastatic dissemination capacity of NSCLC. [Display omitted] [ABSTRACT FROM AUTHOR]

Critical-sized diaphysis defects are complicated by inherent sub-optimal healing conditions. The two-staged induced membrane technique has been used to treat these challenging defects since the 1980's. It involves temporary implantation of a membrane-inducing spacer and subsequent bone graft defect filling. A single-staged, graft-independent technique would reduce both socio-economic costs and patient morbidity. Our aim was to enable such single-staged approach through development of a strong bioactive glass scaffold that could replace both the spacer and the graft filling. We constructed amorphous porous scaffolds of the clinically used bioactive glass S53P4 and evaluated them in vivo using a critical-sized defect model in the weight-bearing femur diaphysis of New Zealand White rabbits. S53P4 scaffolds and standard polymethylmethacrylate spacers were implanted for 2, 4, and 8 weeks. Induced membranes were confirmed histologically, and their osteostimulative activity was evaluated through RT-qPCR of bone morphogenic protein 2, 4, and 7 (BMPs). Bone formation and osseointegration were examined using histology, scanning electron microscopy, energy-dispersive X-ray analysis, and micro-computed tomography imaging. Scaffold integration, defect union and osteosynthesis were assessed manually and with X-ray projections. We demonstrated that S53P4 scaffolds induce osteostimulative membranes and produce osseointegrative new bone formation throughout the scaffolds. We also demonstrated successful stable scaffold integration with early defect union at 8 weeks postoperative in critical-sized segmental diaphyseal defects with implanted sintered amorphous S53P4 scaffolds. This study presents important considerations for future research and the potential of the S53P4 bioactive glass as a bone substitute in large diaphyseal defects. Surgical management of critical-sized diaphyseal defects involves multiple challenges, and up to 10% result in delayed or non-union. The two-staged induced membrane technique is successfully used to treat these defects, but it is limited by the need of several procedures and bone graft. Repeated procedures increase costs and morbidity, while grafts are subject to donor-site complications and scarce availability. To transform this two-staged technique into one graft-independent procedure, we developed amorphous porous scaffolds sintered from the clinically used bioactive glass S53P4. This work constitutes the first evaluation of such scaffolds in vivo in a critical-sized diaphyseal defect in the weight-bearing rabbit femur. We provide important knowledge and prospects for future development of sintered S53P4 scaffolds as a bone substitute. [Display omitted] [ABSTRACT FROM AUTHOR]

Summary: Bone morphogenic proteins (BMPs) are members of the transforming growth factor β (TGF-β) cytokine family promoting differentiation, homeostasis, and self-renewal of multiple tissues. We show that signaling through the bone morphogenic protein receptor 1α (BMPR1α) sustains expression of FOXP3 in Treg cells in peripheral lymphoid tissues. BMPR1α signaling promotes molecular circuits supporting acquisition and preservation of Treg cell phenotype and inhibiting differentiation of pro-inflammatory effector Th1/Th17 CD4+ T cell. Mechanistically, increased expression of KDM6B (JMJD3) histone demethylase, an antagonist of the polycomb repressive complex 2, underlies lineage-specific changes of T cell phenotypes associated with abrogation of BMPR1α signaling. These results reveal that BMPs are immunoregulatory cytokines mediating maturation and stability of peripheral FOXP3+ regulatory T cells (Treg cells) and controlling generation of iTreg cells. Thus, we establish that BMPs, a large cytokine family, are an essential link between stromal tissues and the adaptive immune system involved in sustaining tissue homeostasis by promoting immunological tolerance.

Endothermy requires a source of endogenous heat production. In birds, this is derived primarily from shivering, but in mammals it is mostly non-shivering thermogenesis (NST). Brown adipose tissue (BAT) is a specialized tissue found in Eutherian mammals that is the source of most NST. Heat production in BAT depends primarily on the activity of uncoupling protein 1 (UCP1), which decouples transport of protons across the inner mitochondrial membrane from synthesis of ATP. UCP1 and hence heat production of BAT is regulated by many factors. In this paper we discuss the main factors activating UCP1 and increasing heat production. Probably the most well-known activator is the catecholamine norepinephrine (NE) which is released from sympathetic nerve endings and binds to adrenergic receptors that are abundantly expressed on BAT. NE stimulates release of free-fatty acids. It was previously thought that such FFAs were essential for activation of UCP1. However recent work has suggested intracellular lipolysis is not essential and FFAs can be derived from extracellular sources. Thyroid hormones also exert impacts on metabolic rate via effects on brown adipocytes which express type 2 deiodinase. Knocking out DIO2 makes mice cold intolerant. Parathyroid hormone appears to also be a potent regulator of BAT activity and may be an important mediator of elevated expenditure during cancer cachexia, although this is disputed by observations that cachexia wasting is not blunted in UCP1 KO mice. Cardiac natriuretic peptides have also been implicated in regulating BAT thermogenesis and the interconversion of beige adipocytes from their white to brown form. Activation of BAT thermogenesis may be an important component of the post-ingestion rise in heat production. Recent work suggests the gut derived hormone secretin may play a key role in this effect, directly linking BAT activation to the alimentary tract. Not only gut hormones but also metabolites derived from gut microbiota such as butyrate may be an important activator of BAT during cold exposure. Additional regulatory factors include bone morphogenic proteins, fibroblast growth factor 21, Vascular endothelial growth factors and transient receptor potential vanilloid receptors which are important components of thermal sensing and hence how brown adipose tissue responds to the cold. In the future the main challenge is to understand how these regulatory factors combine with each other and with inhibitory factors to control heat production from BAT, and what their relative importance is in differing circumstances. Knocking out UCP1 has revealed other sources of heat production in BAT including creatine-dependent cycles and a futile cycle of Ca2+ shuttling into and out of the endoplasmic reticulum via the SERCA and ryanodine receptors. [ABSTRACT FROM AUTHOR]

Abstract Multiple myeloma (MM) is characterised by destructive lytic bone disease, caused by induction of bone resorption and impaired bone formation. Our understanding of the molecular mechanisms responsible for osteoblast suppression, are limited. Using the 5T2MM murine model of MM we have previously shown that suppression of the activity of a known inhibitor of bone formation Dikkopf-1 (Dkk1) prevents the development of lytic bone disease. Here we have demonstrated that another potential inhibitor of bone formation, sclerostin domain containing 1 (Sostdc1) is expressed at low levels in MM and osteoblast lineage cells when these cells are grown separately in cell culture but its expression is significantly induced in both cell types when these cells are in contact. The distribution of Sostdc1 staining in bones infiltrated with 5TGM1 myeloma cells in vivo suggested its presence in both myeloma and osteoblast lineage populations when in close proximity. We have also shown that recombinant Sostdc1 inhibits both bone morphogenic proteins (BMP2 and 7) and Wnt signalling in primary osteoblasts and suppresses differentiation of these cells. Together, these findings suggest that Sostdc1 expression in 5TGM1-infiltrated bones as a result of the interaction between myeloma and osteoblast lineage populations, could result in suppression of osteoblast differentiation. Highlights • Sostdc1 is a potent suppressor of osteoblast differentiation. • Sostdc1in osteoblast and myeloma cells is induced when these cells interact. • Sostdc1 down regulates Wnt-BMP signalling crosstalk in osteoblasts. • Sostdc1 is present in myeloma-infiltrated bone disease and not present in normal bone. [ABSTRACT FROM AUTHOR]

Background: BMPs play important roles in normal bone development and regulation of bone repair by their ability to stimulate osteogenesis,cell differentiation and apposition of bone matrix. Aim of study: to find role for the application of BMP4 in bone defect with expression of BMP7 by newly formed bone. Materials and Method: Twenty male Wistar rats were used to create a drill-hole injury (3mm) bone defects in femur,one in the left side represented the control,while the right side represented the experimental. The study groups include: • Control group,the bone defect was left without treatment . • Experimental group,the bone defect treated with 0.5 μl of BMP4. Bone repair was examined histologyically and immunohistochemically for the expression of BMP7 at the postoperative periods 14 and 28 day . Result: Show increased bone formation with proceeding time postoperatively for both study groups,although experimental group illustrates more bone apposition that filled the defect at 28 day.Moreover intense positive expression of BMP7 by stromal and bone cells were illustrated in experimental group with high significant differences in comparisum to control. Conclusions: BMP4 seems to play an important role in bone repair; induced expression of BMP7 correlates with the bone repair outcome. [ABSTRACT FROM AUTHOR]

The aim of the present study was to test the hypothesis that immobilisation of bone morphogenic proteins on the surface of titanium implants through nano-anchored oligonucleotides can enhance peri-implant bone formation. Non-coding 60-mer DNA oligonucleotides (ODN) were anchored to the surface of custom made sandblasted acid etched (SAE) titanium screw implants through anodic polarisation, gamma-sterilised with a standard dose of 25 kGy, and were hybridised with complementary 30-mer strands of DNA oligonucleotides conjugated to rhBMP2. Blank SAE implants, SAE implants with nano-anchored ODN and SAE implants with nano-anchored ODN and non-conjugated rhBMP2 served as controls. The implants were inserted into the tibiae of 36 Sprague Dawley rats. Perforations at the head and the tip of the implants allowed for bone ingrowth. Bone ingrowth into perforations and bone implant contact (BIC) as well as bone density (BD) at a distance of 200 µm from the implant surface were assessed after 1 , 4 and 13 weeks. Implants with nano-anchored ODN strands hybridised with conjugated rhBMP2 exhibited enhanced bone ingrowth into the perforations and increased BIC after 1 week as well as increased BIC after 4 weeks compared to controls. No difference was seen after 13 weeks. Bone density around the outer implant surface did not differ significantly at any of the intervals. It is concluded that rhBMP2 immobilised on the surface of titanium implants through nano-anchored oligonucleotide strands can enhance bone implant contact. The conditions of sterilisation tested allowed for handling under clinically relevant conditions.

Abstract Transverse palatal distraction is a biological process of regenerating new bone and enveloping soft tissues in the maxillary palate region. This technique is similar to Osteo-distraction (OD) procedure for bone lengthening in which gradual and controlled traction forces are applied on the osteotomy gaps to produce new bone in between the surgically separated bone segments. This review describes the different phases after osteotomy and the biological process involved during the new bone and soft tissue formation. The mechanical environment formed in the distraction area is due to the traction forces by the distractor appliance. This environment stimulates differentiation of pluripotent cells, neovascularization, osteogenesis and remodeling of newly formed bone. The role of different pro-inflammatory cytokines, interleukins, bone morphogenic proteins, transforming growth factors, fibroblast growth factors-2) and extracellular matrix proteins (osteonectin, osteopontin) during the distraction phases has been described in detail. Also, an important note on the nutritional aspect during Osteo-distraction will benefit the clinicians to guide their patients after osteotomy throughout the distraction process. [ABSTRACT FROM AUTHOR]

Biomechanical properties of mammalian bones, such as strength, toughness, and plasticity, are essential for understanding how microscopic-scale mechanical features can link to macroscale bones' strength and fracture resistance. We employ Brillouin light scattering (BLS) microspectroscopy for local assessment of elastic properties of bones under compression and the efficacy of the tissue engineering approach based on heparin-conjugated fibrin (HCF) hydrogels, bone morphogenic proteins, and osteogenic stem cells in the regeneration of the bone tissues. BLS is noninvasive and label-free modality for probing viscoelastic properties of tissues that can give information on structure-function properties of normal and pathological tissues. Results showed that MCS and BPMs are critically important for regeneration of elastic and viscous properties, respectively, HCF gels containing combination of all factors had the best effect with complete defect regeneration at week nine after the implantation of bone grafts and that the bones with fully consolidated fractures have higher values of elastic moduli compared with defective bones. [ABSTRACT FROM AUTHOR]

Statins, the lipid-lowering drugs, provide an important and effective approach for the treatment of hyperlipidemia and arteriosclerosis. They function by reducing the blood cholesterol levels which came as a marked discovery to intervene in cardiovascular and cerebrovascular diseases related to increased lipid levels. Their long-term systemic administration in humans has been shown to result in increased bone mineral density. In recent scenario, statins thus modulate bone metabolism exhibiting antibone resorbing properties by upregulating the bone morphogenic proteins and blocking the intermediate metabolites of the mevalonate pathway, made evident by various in vivo and in vitro studies thus providing a new direction in the field of periodontal regeneration. Statins also offered the added advantage of anti-inflammatory and antioxidant properties. Thus, the use of statins both systemically and locally gained wide acceptance by the periodontists as they have shown to increase the bone mineral density and may be effective for periodontal regeneration by stimulation of regenerative factors. This article reviews the beneficial effect of statins and examines their potential role in regenerative periodontal therapy.

Sabe-se que Bone morphogenic proteins (BMP) são promotores de osteogênese, mas pesquisas ainda estão sendo feitas no intuito de descobrir sua atuação clínica na reparação de fraturas. As dificuldades inerentes da reparação de fraturas de rádio-ulna de cães abaixo de 6 quilos são conhecidas, principalmente, com a ocorrência freqüente de não-união óssea devido a pouca vascularização da porção distal do radio. Tendo em vista esta realidade objetivou-se a comparação da velocidade de formação de calo ósseo entre o tratamento com placas e parafusos e tratamento com placas e parafusos associados a BMP. Foram realizadas 33 osteossinteses de regiões distais de rádio-ulna de cães, sendo 17 animais do grupo controle (tratamento com placas e parafusos) e 16 animais do grupo BMP (tratamento com placas e parafusos com adição de proteína morfogenética óssea BMP). Avaliou-se, comparativa-mente, o tempo de formação de calo ósseo, por exames radiográficos, aos 30, 60, 90,120, 180 e 210 dias de pós-operatório. Foi encontrada a média de tempo de cicatrização de 127,5 +/- 34,15 dias no grupo controle e, no grupo tratado com a proteína morfogenética óssea, a média foi de 32 +/- 15 dias. Com isto pode-se concluir que as fraturas distais de rádio e ulna, em cães menos de 6 kg, tratadas com proteína morfogenética óssea sofreram redução significativa do tempo de formação de calo ósseo.It is well known that bone morphogenic proteins (BMP) cause osteogenesis, yet clinical research must be performed in order to really show their benefits. Animals weighing less than 6 kg show well known difficulties regarding radius and ulna fracture repair mainly with bone non-union, due to poor vascularization of the distal portion of the radius. Therefore this study aimed to compare the velocity of bone callus formation in the treatment of fracture repair with plates and screws alone or with plates and screws plus BMP. Thirty three dogs with radius and ulna fractures were distributed into two groups, where animals of the control group received the conservative treatment performed with screws and plates alone, whilst the other group received the conservative treatment and BMP. The time of bone callus formation was evaluated comparatively through radiographic exams 30, 60, 90, 120, 180 and 210 days after the surgical procedure. Animals treated with BMP showed a healing time of 32±15 days, which was significantly different (p

Bone morphogenic proteins (BMPs) signaling blockade induce neurogenesis and oligodendrogenesis. Differential screening-selected gene aberrative in neuroblastoma (DAN) is a glycoprotein that antagonizes BMPs. We found that DAN levels were higher in CSF compared to serum in all participants. CSF-DAN levels were elevated in RR-and progresssive MS patients compared to controls. Moreover, serum-DAN levels were reduced in those patients, but elevated in IFN-β1a treated patients. The main source of DAN is apparently CNS- resident cells. The enhanced levels of CSF-DAN in MS patients suggest a tendency to induce neurogenesis/oligodendrogenesis in the patients CNS. Our results suggest an unreported mode of action of IFN-β1a. [ABSTRACT FROM AUTHOR]

We describe a case of extensive osteonecrosis of the mandible after a dental extraction in a 71-year-old woman who was taking alendronic acid (Fosamax ® , Merck) for osteoporosis. Bone damaged by bisphosphonate-related osteonecrosis of the jaw (BRONJ), also now known as medication-related osteonecrosis of the jaw (MRONJ), can be regenerated and filled with endosseous implants using non-vascularised autologous grafts. [ABSTRACT FROM AUTHOR]

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-β) superfamily of signaling molecules. In addition to protean roles in embryonic development, germ-line specification, and cellular differentiation, a central role in iron homeostasis has recently been demonstrated for certain BMPs. Specifically, BMP6 serves to relate hepatic iron stores to the hepatocellular expression of the iron-regulatory hormone hepcidin. This regulation occurs via cellular SMAD-signaling molecules and is strongly modulated by the BMP coreceptor hemojuvelin (HJV). Mutations in certain genes influencing signaling to hepcidin via the BMP/SMAD pathway are associated with human disorders of iron metabolism, such as hereditary hemochromatosis and iron-refractory iron-deficiency anemia. Evidence suggests that signals in addition to iron stores influence hepcidin expression via the BMP/SMAD pathway. This review summarizes the details of BMP/SMAD signaling, with a particular focus on its role in iron homeostasis and iron-related diseases. [ABSTRACT FROM AUTHOR]

Bone morphogenic proteins (BMPs) and the Notch pathway regulate quiescence and selfrenewal of stem cells of the subventricular zone (SVZ), an adult neurogenic niche. Here we analyze the role at the intersection of these pathways of Tis21 (Btg2/PC3), a gene regulating proliferation and differentiation of adult SVZ stem and progenitor cells. In Tis21- null SVZ and cultured neurospheres, we observed a strong decrease in the expression of BMP4 and its effectors Smad1/8, while the Notch anti-neural mediators Hes1/5 and the basic helix-loop-helix (bHLH) inhibitors Id1-3 increased. Consistently, expression of the proneural bHLH gene NeuroD1 decreased. Moreover, cyclins D1/2, A2, and E were strongly up-regulated. Thus, in the SVZ Tis21 activates the BMP pathway and inhibits the Notch pathway and the cell cycle. Correspondingly, the Tis21-null SVZ stem cells greatly increased; nonetheless, the proliferating neuroblasts diminished, whereas the post-mitotic neuroblasts paradoxically accumulated in SVZ, failing to migrate along the rostral migratory stream to the olfactory bulb. The ability, however, of neuroblasts to migrate from SVZ explants was not affected, suggesting that Tis21-null neuroblasts do not migrate to the olfactory bulb because of a defect in terminal differentiation. Notably, BMP4 addition or Id3 silencing rescued the defective differentiation observed in Tis21-null neurospheres, indicating that they mediate the Tis21 pro-differentiative action. The reduced number of granule neurons in the Tis21-null olfactory bulb led to a defect in olfactory detection thres hold, without effect on olfactory memory, also suggesting that within olfactory circuits new granule neurons play a primary role in odor sensitivity rather than in memory. [ABSTRACT FROM AUTHOR]

Abstract: Increasing evidence supports the theory that tumor growth, homeostasis, and recurrence are dependent on a small subset of cells with stem cell properties, redefined cancer initiating cells (CICs) or cancer stem cells. Bone morphogenetic proteins (BMPs) are involved in cell-fate specification during embryogenesis, in the maintenance of developmental potency in adult stem cells and may contribute to sustain CIC populations in breast carcinoma. Using the mouse A17 cell model previously related to mesenchymal cancer stem cells and displaying properties of CICs, we investigated the role of BMPs in the control of breast cancer cell plasticity. We showed that an autocrine activation of BMP signaling is crucial for the maintenance of mesenchymal stem cell phenotype and tumorigenic potential of A17 cells. Pharmacological inhibition of BMP signaling cascade by Dorsomorphin resulted in the acquisition of epithelial-like traits by A17 cells, including expression of Citokeratin-18 and E-cadherin, through downregulation of Snail and Slug transcriptional factors and Cyclooxygenase-2 (COX2) expression, and in the loss of their stem-features and self-renewal ability. This phenotypic switch compromised A17 cell motility, invasiveness and in vitro tumor growth. These results reveal that BMPs are key molecules at the crossroad between stemness and cancer. [Copyright &y& Elsevier]

Highlights: [•] The regulation of the osteogenic effects of BMPs is important in bone physiology and pathology. [•] Receptors tyrosine kinase reduce BMP2-induced osteoblastic differentiation of mesenchymal stem cells. [•] Receptors tyrosine kinase interfere with Smad signaling by activating JNK and inhibiting PI3K/GSK3. [•] GSK3 activity is a key regulator of Smad signaling in human mesenchymal stem cells. [•] A rationale for understanding difficulties in the use of recombinant BMPs in orthopedic treatments is proposed. [ABSTRACT FROM AUTHOR]

The seronegative spondyloarthopathies (SpA) share certain common articular and peri-articular features that differ from rheumatoid arthritis (RA) and other forms of inflammatory arthritis. These include the tendency of the SpAs to involve the axial skeleton in addition to the diarthrodial joints, and the prominent involvement of the extra-articular entheses (sites of ligamentous and tendon insertion), which are not common sites of primary pathology in RA and other inflammatory arthropathies. The differential anatomic sites of bone pathology in the SpAs in comparison to the other forms of arthritis suggest that the underlying pathogenic processes and cellular and molecular mechanisms that account for the peri-articular bone pathology involve different underlying disease mechanisms. This review will highlight the molecular and cellular processes that are involved in the pathogenesis of the skeletal pathology in the SpAs, and provide evidence that many of the factors involved in regulation of bone cell function exhibit potent immune-regulatory activity, providing support for the general concept of osteoimmunology. [ABSTRACT FROM AUTHOR]

Abstract: A great deal is known about the molecular mechanisms regulating terminal differentiation of pre-adipocytes into mature adipocytes. In contrast, the knowledge about pathways that trigger commitment of mesenchymal stem cells into the adipocyte lineage is fragmented. In recent years, the role of members of the bone morphogenic protein family in regulating the early steps of adipogenesis has been the focus of research. Findings based on these studies have also highlighted an unexpected role for some bone morphogenic protein in energy homeostasis via regulation of adipocyte development and function. This review summarizes the knowledge about bone morphogenic proteins and their role in adipocyte commitment and regulation of whole body energy homeostasis. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease. [Copyright &y& Elsevier]

Abstract: A large body of evidence supports an important role of bone morphogenic proteins (BMPs) pathways in skeletal development in the embryo. BMPs are also involved in skeletal homeostasis and diseases in the adult. They were first identified as major bone anabolic agents and recent advances indicate that they also regulate osteoclastogenesis and joint components via multiple cross-talks with other signaling pathways. This review attempts to integrate these data in the pathogenesis of bone and joints diseases, such as osteoporosis, fracture healing, osteoarthritis, inflammatory arthritis, or bone metastasis. The use of recombinant BMPs in bone tissue engineering and in the treatment of skeletal diseases, or future therapeutic strategies targeting BMPs signal and its regulators, will be discussed based on these considerations. [Copyright &y& Elsevier]

Bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor beta superfamily. This literature review focuses on the molecular biology of BMPs, their mechanism of action, and subsequent applications. It also discusses uses of BMPs in the fields of dentistry and orthopedics, research on methods of delivering BMPs, and their role in tissue regeneration. BMP has positive effects on bone grafts, and their calculated and timely use with other growth factors can provide extraordinary results in fractured or nonhealing bones. Use of BMP introduces new applications in the field of implantology and bone grafting. This review touches on a few unknown facts about BMP and this ever-changing field of research to improve human life. [ABSTRACT FROM AUTHOR]

Abstract: Understanding the interactions between growth factors and bone morphogenic proteins (BMPs) signaling remains a crucial issue to optimize the use of human mesenchymal stem cells (HMSCs) and BMPs in therapeutic perspectives and bone tissue engineering. BMPs are potent inducers of osteoblastic differentiation. They exert their actions via BMP receptors (BMPR), including BMPR1A, BMPR1B and BMPR2. Fibroblast growth factor 2 (FGF2) is expressed by cells of the osteoblastic lineage, increases their proliferation and is secreted during the healing process of fractures or in surgery bone sites. We hypothesized that FGF2 might influence HMSC osteoblastic differentiation by modulating expressions of BMPs and their receptors. BMP2, BMP4, BMPR1A and mainly BMPR1B expressions were up-regulated during this differentiation. FGF2 inhibited HMSCs osteoblastic differentiation and the up-regulation of BMPs and BMPR. This effect was prevented by inhibiting the ERK or JNK mitogen-activated protein kinases which are known to be activated by FGF2. These data provide a mechanism explaining the inhibitory effect of FGF2 on osteoblastic differentiation of HMSCs. These crosstalks between growth and osteogenic factors should be considered in the use of recombinant BMPs in therapeutic purpose of fracture repair or skeletal bioengineering. [Copyright &y& Elsevier]

Segment transport for reconstruction of long bone defects >2 cm long is a safe procedure for restoration of length of anatomical extremities. Insufficient regeneration is a regularly occurring but rare complication. Exact figures on the frequency are lacking in the literature. Because mesenchymal stem cells (MSC) can be detected in distraction osteogenesis, bone growth factors can be detected in callus distraction and bone morphogenic protein (BMP) stimulates angiogenesis and differentiation of MSCs to osteogenic cell lines, preliminary attempts were made to treat disorders in callus maturation with administration of BMP. This article describes investigations on whether regeneration insufficiency after callus distraction can be successfully treated by administration of BMP. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to test the hypothesis that oligonucleotides can be used for anchorage and slow release of osteogenic growth factors such as BMP to enhance the osteogenic activity of a titanium implant surface. Strands of 60-mer non-coding DNA oligonucleotides (ODN) were bound to an acid-etched sandblasted cp Ti-surface by nanomechanical fixation using anodic polarization. RhBMP2 that had been conjugated to complementary strands of DNA oligonucleotides was then bound to the anchored ODN strands by hybridization. Binding studies showed a higher binding capacity compared to non-conjugated BMP2. Long term release experiments demonstrated a continuous release from all surfaces that was lowest for the conjugated BMP2 bound to the ODN anchor strands. Proliferation of human bone marrow stroma cells (hBMSC) was significantly increased on these surfaces. Immunofluorescence showed that hBMSC grown on surfaces coated with specifically bound conjugated BMP2 developed significantly higher numbers of focal adhesion points and exhibited significantly higher levels of transcription of osteogenic markers alkaline phosphatase and osteopontin at early intervals. Biological activity (induction of alkaline phosphatase) of conjugated BMP2 released from the surface was comparable to released non-conjugated BMP2, indicating that conjugation did not negatively affect the activity of the released molecules. In conclusion the present study has shown that BMP2 conjugated to ODN strands and hybridized to complementary ODN strands anchored to a titanium surface has led to slow growth factor release and can enhance the osteogenic activity of the titanium surface. [Copyright &y& Elsevier]

Background: As major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor β (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma. In order to uncover their possible implication, the aim of this study was to perform a systematic quantitative study of the expression of BMPs, TGFBs and their receptors and to assess activity of the corresponding pathways in central chondrosarcoma. Methods: Gene expression analysis was performed by quantitative RT-PCR in 26 central chondrosarcoma and 6healthy articular cartilage samples. Expression of endoglin and nuclear localization of phosphorylated Smad1/5/8 and Smad2 was assessed by immunohistochemical analysis. Results: The expression of TGFB3 and of the activin receptor-like kinase ALK2 was found to be significantly higher in grade III compared to grade I chondrosarcoma. Nuclear phosphorylated Smad1/5/8 and Smad2 were found in all tumors analyzed and the activity of both signaling pathways was confirmed by functional reporter assays in 2 chondrosarcoma cell lines. Immunohistochemical analysis furthermore revealed that phosphorylated Smad1/5/8 and endoglin expression were significantly higher in high-grade compared to low-grade chondrosarcoma and correlated to each other. Conclusions: The BMP and TGFβ signaling pathways were found to be active in central chondrosarcoma cells. The correlation of Smad1/5/8 activity to endoglin expression suggests that, as described in other cell types, endoglin could enhance Smad1/5/8 signaling in high-grade chondrosarcoma cells. Endoglin expression coupled to Smad1/5/8 activation could thus represent a functionally important signaling axis for the progression of chondrosarcoma and a regulator of the undifferentiated phenotype of high-grade tumor cells. [ABSTRACT FROM AUTHOR]

Abstract: One of the mechanisms known to play a key role in neuronal and oligodendroglial fate specification of neural stem cells (NSCs) is restriction of bone morphogenic proteins (BMP) signaling by BMP antagonists. Here, we demonstrate that follistatin mRNA and protein secreted levels in peripheral blood mononuclear cells (PBMCs) of relapsing–remitting multiple sclerosis (RR-MS) patients are significantly reduced compared to healthy controls (HC). We also observed a different profile of regulation mechanisms. Follistatin was similarly expressed and secreted by T lymphocytes and monocytes among the PBMCs of HC, and follistatin upregulation of HC was subjected to stimulation with both LPS and TNF-α. Among PBMCs of RR-MS patients, however, follistatin was found to be downregulated in their monocytes and unresponsive to stimulation with either LPS or TNF-α. Our results may shed some light on the mechanisms involved in remyelination failure in MS, which may be related to the inability of RR-MS patients'' immune cells to provide a sufficient pro-neurogenic and oligodendrogenic niche, by expressing and secreting follistatin, in addition to the previously described noggin reduced expression. Our results indicate that the low expression of follistatin in immune cells of patients with RR-MS is a result of the altered immunoregulation of monocytes in these patients. [Copyright &y& Elsevier]

Abstract: This review, the second in a series of three editorials, focuses on the problems of translating basic scientific research on induction of bone into reliable clinical applications. [ABSTRACT FROM AUTHOR]

There is mounting evidence that innate and adaptive immunity are critical for periodontal disease-mediated bone resorption. These studies examined the role of B and CD4 T cells in adaptive immunity of rats infected with Aggregatibacter actinomycetemcomitans ( Aa). Sprague-Dawley male rats were fed Aa-containing mash or control-mash for 2 weeks. B and CD4 T cells were obtained from draining lymph nodes at 2, 4 and 12 weeks, postinoculation. Quantitative polymerase chain reaction-based messenger RNA expression was conducted for 89 cytokine family genes. Disease-relevance of the differentially expressed genes was assessed using a biological interaction pathway analysis software. B and CD4 T cells of Aa-infected rats increased and were activated, resulting in enhanced isotype-switched serum immunoglobulin G by 2 weeks postinoculation. Bone resorption was evident 12 weeks after Aa-feeding. In B cells, interleukin-2 (IL-2), macrophage-inhibiting factor, IL-19, IL-21, tumor necrosis factor (TNF), CD40 ligand (CD40L), CD70, bone morphogenetic protein 2 (BMP2), BMP3, and BMP10 were upregulated early; while IL-7, Fas ligand (FasL), small inducible cytokine subfamily E1, and growth differentiation factor 11 (GDF11; BMP11) were upregulated late (12 weeks). BMP10 was sustained throughout. In CD4 T cells, IL-10, IL-16, TNF, lymphotoxin-beta (LTβ), APRIL, CD40L, FasL, RANKL and osteoprotegerin were upregulated early, whereas IL-1β, IL-1RN, IL-1F8, IL-24, interferon-α1, GDF11 (BMP11), and GDF15 were upregulated late (12 weeks). Adaptive immunity appears crucial for bone resorption. Several of the deregulated genes are, for the first time, shown to be associated with bone resorption, and the results indicate that activated B cells produce BMP10. The study provides a rationale for a link between periodontal disease and other systemic diseases. [ABSTRACT FROM AUTHOR]

Abstract: Genetic hemochromatosis (GH) encompass a heterogeneous group of disorders, which is related to hepcidin deficiency (except type 4A of the ferroportin disease), leading to iron overload and eventually organ failure due to inappropriately high intestinal iron absorption. The most frequent entity remains HFE-related hemochromatois associated with the homozygosity for the p.Cys282Tyr mutation in the HFE gene (C282Y mutation), first identified in 1996. Several other genetic causes have been identified since 2000, often referred to as non-HFE hemochromatosis, resulting from mutations in genes involved in the regulation of iron homeostasis, such as transferrin receptor 2 (TRF2, type 3 GH), hepcidin (HAMP, type 2 GH), hémojuvelin (HJV, type 2 GH), ferroportin (SLC40A1, type 4 GH). Iron excess is due to deficiencies in either hepcidin, regulated by BMP6, or ferroportin (type 4A GH). So, several genes underlie the various forms of the disease, which have similar pathophysiological profiles but distinct clinical presentations. Additional genetic and environmental factors can modify the severity of the disease. The introduction of molecular tests into clinical practice has provided a tool for early diagnosis of these genetic diseases. [Copyright &y& Elsevier]

Abstract: The last few decades of basic science research have provided an increased understanding of the role of osteogenic glycoproteins in bone formation. The isolation of such molecules now permits de novo orthotopic induction with increasing evidence of the ability to also induce bone growth in heterotopic sites. The current editorial focuses on the basic science of bone induction with two subsequent issues dedicated to the translation of these principles into both animal subjects and human clinical applications. [Copyright &y& Elsevier]

Bone marrow mesenchymal stem cells (MSCs) are multipotent cells, which among other cell lineages, give rise to adipocytes and osteoblasts. Within the bone marrow, the differentiation of MSCs into adipocytes or osteoblasts is competitively balanced; mechanisms that promote one cell fate actively suppress mechanisms that induce the alternative lineage. This occurs through the cross talk between complex signaling pathways including those derived from bone morphogenic proteins (BMPs), winglesstype MMTV integration site (Wnt) proteins, hedgehogs, delta/jagged proteins, fibroblastic growth factors (FGF), insulin, insulin-like growth factors (IGF), and transcriptional regulators of adipocyte and osteoblast differentiation including peroxisome proliferator-activated receptor-γ (PPARγ) and runt-related transcription factor 2 (Runx2). Here, we discuss the molecular regulation of bone marrow adipogenesis with emphasis on signals that interact with osteoblastogenic pathways and highlight the possible therapeutic implications of these interactions. [ABSTRACT FROM AUTHOR]

Objectives: The present study was conducted to test the hypothesis that preshaped polylactic acid (PLA) implants loaded with recombinant human bone morphogenic protein 2 (rhBMP-2) can induce bone formation in a rat ectopic model. Materials and methods: Two groups of porous cylindrical poly-dl-lactic acid implants of 8-mm diameter were produced by gas foaming with CO2, incorporating 48 and 96 μg rhBMP-2, respectively, into each implant. Blank PLA implants were used as controls. The release of BMPs and the induction of alkaline phosphatase were assessed in vitro. Osteoinduction in vivo was tested by insertion of 15 implants from each group into the gluteal muscles of Wistar rats. Five implants from each group were retrieved after 6, 13 and 26 weeks and assessed using flat panel volume detector computed tomography and light microscopy. Results: Both groups of implants showed increased release of rhBMP-2 during the first 24–48 h, with a slightly higher amount being released from the implants with 48 μg. Release during subsequent intervals was <100 ng/72 h in the low-concentration group and >100 ng in the group with 96 μg rhBMP-2. Implants with 95 μg rhBMP-2 exhibited bone formation in vivo on the outside of the implants across the observation period of 26 weeks with invasion of bone into the pores, whereas implants with 48 μg rhBMP-2 failed to induce the formation of bone tissue. No bone formation was found in the control implants. Conclusions: The results suggest that release rates of rhBMP-2 for ectopic bone induction have to be >100 ng/72 h to maintain the osteoinductive activity of the tested porous PLA implants. This slow release system may have impact on alveolar bone augmentation procedures when used as individually preformed osteoinductive implants. [ABSTRACT FROM AUTHOR]

Primordial germ cells comprise a privileged cellular class with in the embryo charged with the elite task of maintaining species longevity. While in lower organisms germ-cell fate is determined by the allocation of germ plasm, mammalian germ-line differentiation requires extracellular signals that converge upon the proximal epiblast. Studies using mutant mice or explanted embryos have identified some of the factors controlling primordial germ-cell specification, such as members of the BMP family, but considerable gaps still exist in our understanding of the complete signaling network. Comprehensive investigations of mammalian germline specification have been hampered by the inaccessibility of this cell population in the early embryo. Recently, however, several labs including our own have derived primordial germ cells from embryonic stem cells in vitro, thus providing a powerful new technique for the study of germ cells. In this review the different methods used for the in vitro generation of germ cells and how these techniques may be improved and applied to further advance our knowledge of germ-cell biology are discussed. [ABSTRACT FROM AUTHOR]

The aim of the present study was to test the hypothesis that immobilization of bone morphogenic protein (BMP2) on the surface of titanium implants can enhance peri-implant bone formation. Ten adult female foxhounds received experimental titanium screw implants in the mandible 3 months after removal of all premolar teeth. Three types of implant surfaces were evaluated in each animal: (i) implants with machined titanium surface, (ii) implants coated with collagen I, (iii) implants coated with collagen I, chondroitin sulphate (CS) and BMP2. Peri-implant bone regeneration was assessed using histomorphometry after 1 and 3 months in five dogs each by measuring bone–implant contact (BIC) and the volume density of the newly formed peri-implant bone (BVD). After 1 month, there was no significant enhancement in BIC values but volume density of the newly formed peri-implant bone was significantly higher in the two groups of coated implants. No significant difference was found between collagen and BMP2 coating. After 3 months, BIC was significantly higher in both collagen and BMP2-coated implants compared with implants with machined surfaces. Peri-implant BVD was also significantly increased in coated implants in comparison with machined surfaces. It was concluded that collagen coating of dental screw implants can enhance BIC and peri-implant bone formation. Addition of BMP2 does not increase peri-implant bone formation in the present application. [ABSTRACT FROM AUTHOR]

Megalin is a low-density lipoprotein receptor-related protein (LRP2) expressed in the neuroepithelium and the yolk sac of the early embryo. Absence of megalin expression in knockout mice results in holoprosencephaly, indicating an essential yet unidentified function in forebrain development. We used mice with complete or conditional megalin gene inactivation in the embryo to demonstrate that expression of megalin in the neuroepithelium but not in the yolk sac is crucial for brain development. During early forebrain development, megalin deficiency leads to an increase in bone morphogenic protein (Bmp) 4 expression and signaling in the rostral dorsal neuroepithelium, and a subsequent loss of sonic hedgehog (Shh) expression in the ventral forebrain. As a consequence of absent SHH activity, ventrally derived oligodendroglial and interneuronal cell populations are lost in the forebrain of megalin-/- embryos. Similar defects are seen in models with enhanced signaling through BMPs, central regulators of neural tube patterning. Because megalin mediates endocytic uptake and degradation of BMP4, these findings indicate a role for megalin in neural tube specification, possibly by acting as BMP4 clearance receptor in the neuroepithelium. [ABSTRACT FROM AUTHOR]