Publications by authors named "Slobodan Vukicevic"

84 Publications

A novel autologous bone graft substitute containing rhBMP6 in autologous blood coagulum with synthetic ceramics for reconstruction of a large humerus segmental gunshot defect in a dog: The first veterinary patient to receive a novel osteoinductive therapy.

Bone Rep 2021 Jun 25;14:100759. Epub 2021 Feb 25.

Laboratory for Mineralized Tissues, Centre for Translational and Clinical Research, School of Medicine, University of Zagreb, Zagreb, Croatia.

Background: Management of large segmental defects is one of the most challenging issues in bone repair biology. Autologous bone graft substitute (ABGS) containing rhBMP6 within autologous blood coagulum (ABC) with synthetic ceramics is a novel biocompatible therapeutic solution for bone regeneration.

Case Presentation: A 2-year old dog was brought to the veterinary clinics due to pain and bleeding from the right front leg after being unintendedly hit by a gunshot. Radiological examination revealed a large, 3 cm long multisegmental defect of the humerus on the right front leg with a loss of anatomical structure in the distal portion of the bone. The defect was treated surgically and an external fixator was inserted to ensure immobilization. Complete lack of bone formation 3 months following surgery required a full reconstruction of the defect site with a novel ABGS (rhBMP6 in ABC with ceramic particles) to avoid front leg amputation. The healing was then followed for the next 16 months. The callus formation was observed on x-ray images 2 months following ABGS implantation. The bone segments progressively fused together leading to the defect rebridgment allowing removal of the external fixator by 4 months after the reconstruction surgery. At the end of the observation period, the function of the leg was almost fully restored while analyses of the humeral CT sections revealed restoration and cortices rebridgment with a renewal of uniform medullary canal including structural reconstruction of the distal humerus.

Conclusion: This large humeral gunshot segmental defect of the front leg in a dog was saved from amputation inducing bone regeneration using a novel ABGS osteoinductive device containing BMP6 in ABC.
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http://dx.doi.org/10.1016/j.bonr.2021.100759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937538PMC
June 2021

Iron overload in aging mice induces exocrine pancreatic injury and fibrosis due to acinar cell loss.

Int J Mol Med 2021 Apr 2;47(4):1-8. Epub 2021 Mar 2.

Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, HR‑10000 Zagreb, Croatia.

The relationship between hemochromatosis and diabetes has been well established, as excessive iron deposition has been reported to result in impaired function of the endocrine and exocrine pancreas. Therefore, the objective of the present study was to analyze the effects of iron accumulation on the pancreata and glucose homeostasis in a bone morphogenetic protein 6‑knockout () mouse model of hemochromatosis. The sera and pancreatic tissues of wild‑type (WT) and mice (age, 3 and 10 months) were subjected to biochemical and histological analyses. In addition, F‑fluorodeoxyglucose biodistribution was evaluated in the liver, muscle, heart, kidney and adipose tissue of both animal groups. The results demonstrated that 3‑month‑old mice exhibited iron accumulation preferentially in the exocrine pancreas, with no signs of pancreatic injury or fibrosis. No changes were observed in the glucose metabolism, as pancreatic islet diameter, insulin and glucagon secretion, blood glucose levels and glucose uptake in the liver, muscle and adipose tissue remained comparable with those in the WT mice. Aging mice presented with progressive iron deposits in the exocrine pancreas, leading to pancreatic degeneration and injury that was characterized by acinar atrophy, fibrosis and the infiltration of inflammatory cells. However, the aging mice exhibited unaltered blood glucose levels and islet structure, normal insulin secretion and moderately increased α‑cell mass compared with those in the age‑matched WT mice. Additionally, iron overload and pancreatic damage were not observed in the aging WT mice. These results supported a pathogenic role of iron overload in aging mice leading to iron‑induced exocrine pancreatic deficiency, whereas the endocrine pancreas retained normal function.
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http://dx.doi.org/10.3892/ijmm.2021.4893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910010PMC
April 2021

Synthetic ceramic macroporous blocks as a scaffold in ectopic bone formation induced by recombinant human bone morphogenetic protein 6 within autologous blood coagulum in rats.

Int Orthop 2020 Oct 14. Epub 2020 Oct 14.

Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia.

Purpose: We have recently developed an autologous bone graft substitute (ABGS) containing recombinant human bone morphogenetic protein 6 (rhBMP6) in autologous blood coagulum (ABC) that induces new bone formation in vivo. In order to improve biomechanical properties of the implant, compression resistant matrix (CRM) consisting of synthetic ceramics in the form of macroporous cylinders was added to the ABGS and we evaluated the biomechanical properties and the quantity and quality of bone formation following subcutaneous implantation in rats.

Methods: ABGS implants containing rhBMP6 in ABC with cylindrical ceramic blocks were implanted subcutaneously (n = 6 per time point) in the axillary region of Sprague-Dawley rats and removed at specified time points (7, 14, 21, 35, and 50 days). The quantity and quality of newly formed bone were analyzed by microCT, histology, and histomorphometric analyses. Biomechanical properties of ABGS formulations were determined by employing the cut test.

Results: MicroCT analyses revealed that ABGS implants induced formation of new bone within ceramic blocks. Histological analysis revealed that on day seven following implantation, the endochondral ossification occupied the peripheral part of implants. On days 14 and 21, newly formed bone was present both around the ceramic block and through the pores inside the block. On both days 35 and 50, cortical bone encircled the ceramic block while inside the block, bone covered the ceramic surface surrounding the pores. Within the osseous circles, there were few trabeculae and bone marrow containing adipocytes. ABGS containing cylindrical ceramic blocks were more rigid and had significantly increased stiffness compared with implants containing ceramic particles as CRM.

Conclusion: We demonstrated that macroporous ceramic blocks in a form of cylinders are promising CRMs with good handling and enhanced biomechanical properties, supporting bone formation with ABGS containing rhBMP6 within autologous blood coagulum. Hence, ABGS containing ceramic blocks should be tested in preclinical models including diaphyseal segmental defects and non-unions in larger animals.
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http://dx.doi.org/10.1007/s00264-020-04847-9DOI Listing
October 2020

Autologous bone graft substitute containing rhBMP6 within autologous blood coagulum and synthetic ceramics of different particle size determines the quantity and structural pattern of bone formed in a rat subcutaneous assay.

Bone 2020 12 23;141:115654. Epub 2020 Sep 23.

Laboratory for Mineralized Tissues, School of Medicine, University of Zagreb, Zagreb, Croatia; Scientific Center of Excellence for Reproductive and Regenerative Medicine, Croatia. Electronic address:

Bone morphogenetic proteins (BMPs) are potent osteoinductive agents for bone tissue engineering. In order to define optimal properties of a novel autologous bone graft substitute (ABGS) containing rhBMP6 within the autologous blood coagulum (ABC) and ceramic particles as a compression resistant matrix (CRM), we explored the influence of their amount, chemical composition and particle size on the quantity and quality of bone formation in the rat subcutaneous assay. Tested ceramic particles included tricalcium phosphate (TCP), hydroxyapatite (HA) and biphasic calcium phosphate ceramic (BCP), containing TCP and HA in 80/20 ratio of different particle sizes (small 74-420 μm, medium 500-1700 μm and large 1000-4000 μm). RhBMP6 was either mixed with ABC or lyophilized on CRM prior to use with ABC. The experiments were terminated on day 21 and implants were analysed by microCT, histology and histomorphometry. Addition of CRM to ABGS containing rhBMP6 in ABC significantly increased the amount of newly formed bone and the optimal CRM/ABC ratio was found to be around 100 mg/500 μL. MicroCT analyses revealed that all tested ABGS formulations induced an extensive new bone formation and there were no differences between the two methods of rhBMP6 application as determined by the bone volume. However, the particle size played a significant role in the quantity and quality of newly formed bone. ABGS containing small particles induced new bone forming a dense trabecular network, cortical bone at the rim, bone and bone marrow in apposition to and in between ceramic particles. ABGS containing medium and large particles also resulted in new bone on the surface of particles as well as inside the pores. Histomorphometric analysis revealed that the ceramics particle size correlated with the quality of trabecular pattern of newly formed bone, bone/bone marrow ratio as observed in apposition and between particles, and the ratio between the cortical and trabecular bone. By employing rat subcutaneous implant assay, we showed for the first time that the size of synthetic ceramics particles affected the osteogenesis as defined by both the quantity and quality of ectopic bone.
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http://dx.doi.org/10.1016/j.bone.2020.115654DOI Listing
December 2020

Editorial - "The role of bone morphogenetic proteins (BMPs) in musculoskeletal biology".

Bone 2020 12 10;141:115622. Epub 2020 Sep 10.

Tissue Engineering Laboratory, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium. Electronic address:

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http://dx.doi.org/10.1016/j.bone.2020.115622DOI Listing
December 2020

Biology of bone morphogenetic protein in bone repair and regeneration: A role for autologous blood coagulum as carrier.

Bone 2020 12 22;141:115602. Epub 2020 Aug 22.

Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia.

BMPs were purified from demineralized bone matrix based on their ability to induce new bone in vivo and they represent a large member of the TGF-β superfamily of proteins. BMPs serve as morphogenic signals for mesenchymal stem cell migration, proliferation and subsequently differentiation into cartilage and bone during embryonic development. A BMP when implanted with a collagenous carrier in a rat subcutaneous site is capable of inducing new bone by mimicking the cellular events of embryonic bone formation. Based on this biological principle, BMP2 and BMP7 containing collagenous matrix as carrier have been developed as bone graft substitutes for spine fusion and long bone fractures. Here, we describe a novel autologous bone graft substitute that contains BMP6 delivered within an autologous blood coagulum as carrier and summarize the biology of osteogenic BMPs in the context of bone repair and regeneration specifically the critical role that carrier plays to support osteogenesis.
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http://dx.doi.org/10.1016/j.bone.2020.115602DOI Listing
December 2020

A novel autologous bone graft substitute comprised of rhBMP6 blood coagulum as carrier tested in a randomized and controlled Phase I trial in patients with distal radial fractures.

Bone 2020 11 27;140:115551. Epub 2020 Jul 27.

Laboratory for Mineralized Tissues, Centre for Translational and Clinical Research, University of Zagreb School of Medicine, Salata 11, 10000 Zagreb, Croatia. Electronic address:

Bone morphogenetic proteins (BMPs) are known to induce new bone formation in vivo but treating trabecular bone defects with a BMP based therapeutic remains controversial. Here, we evaluated the safety and efficacy of a novel Autologous Bone Graft Substitute (ABGS) comprised of recombinant human BMP6 (rhBMP6) dispersed within an autologous blood coagulum (ABC) as a physiological natural carrier in patients with a closed distal radial fracture (DRF). We enrolled 32 patients in a randomized, standard of care (SoC) and placebo (PBO) controlled, double-blinded Phase I First in Human (FiH) clinical trial. ABGS was prepared from peripheral blood as 250 μg rhBMP6/mL ABC or PBO (1 mL ABC containing excipients only) and was administered dorsally via a syringe injection into the fracture site following closed fracture fixation with 3 Kirschner wires. Patients carried an immobilization for 5 weeks and were followed-up for 0 to 26 weeks by clinical examination, safety, serial radiographic analyses and CT. During the 13 weeks follow-up and at 26 weeks post study there were no serious adverse reactions recorded. The results showed that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 32 patients at 13- and 26-weeks following treatment. Pharmacokinetic analyses of plasma from patients treated with ABGS showed no detectable rhBMP6 at any time point within the first 24 h following administration. The CT image and radiographic analyses score from patients treated with AGBS showed significantly accelerated bone healing as compared to PBO and SoC at 5 and 9 weeks (with high effect sizes and P = 0.027), while at week 13 all patients had similar healing outcomes. In conclusion, we show that intraosseous administration of ABGS (250 μg rhBMP6/mL ABC) into the distal radial fracture site demonstrated a good tolerability with no serious adverse reactions as well as early accelerated trabecular bone healing as compared to control PBO and SoC patients.
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http://dx.doi.org/10.1016/j.bone.2020.115551DOI Listing
November 2020

Evaluation of synthetic ceramics as compression resistant matrix to promote osteogenesis of autologous blood coagulum containing recombinant human bone morphogenetic protein 6 in rabbit posterolateral lumbar fusion model.

Bone 2020 11 27;140:115544. Epub 2020 Jul 27.

Laboratory for Mineralized Tissues, School of Medicine, University of Zagreb, Zagreb, Croatia; Scientific Center of Excellence for Reproductive and Regenerative Medicine, Zagreb, Croatia. Electronic address:

Posterolateral lumbar fusion (PLF) is a commonly performed surgical procedure for the treatment of pathological conditions of the lumbosacral spine. In the present study, we evaluated an autologous bone graft substitute (ABGS) containing rhBMP6 in autologous blood coagulum (ABC) and synthetic ceramics used as compression resistant matrix (CRM) in the rabbit PLF model. In the pilot PLF rabbit experiment, we tested four different CRMs (BCP 500-1700 μm, BCP 1700-2500 μm and two different TCP in the form of slabs) which were selected based on achieving uniform ABC distribution. Next, ABGS implants composed of 2.5 mL ABC with 0.5 g ceramic particles (TCP or BCP (TCP/HA 80/20) of particle size 500-1700 μm) and 125 μg rhBMP6 (added to blood or lyophilized on ceramics) were placed bilaterally between transverse processes of the lumbar vertebrae (L5-L6) following exposition and decortication in 12 New Zealand White Rabbits observed for 7 weeks following surgery. Spinal fusion outcome was analysed by μCT, palpatory segmental mobility testing and selected specimens were either tested biomechanically (three-point bending test) and/or processed histologically. The total fusion success rate was 90.9% by both μCT analyses and by palpatory segmental mobility testing. The volume of newly formed bone between experimental groups with TCP or BCP ceramics and the different method of rhBMP6 application was comparable. The newly formed bone and ceramic particles integrated with the transverse processes on histological sections resulting in superior biomechanical properties. The results were retrospectively found superior to allograft devitalized mineralized bone as a CRM as reported previously in rabbit PLF. Overall, this novel ABGS containing rhBMP6, ABC and the specific 500-1700 μm synthetic ceramic particles supported new bone formation for the first time and successfully promoted posterolateral lumbar fusion in rabbits.
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http://dx.doi.org/10.1016/j.bone.2020.115544DOI Listing
November 2020

A cell-based combination product for the repair of large bone defects.

Bone 2020 09 27;138:115511. Epub 2020 Jun 27.

Prometheus, Division of Skeletal Tissue Engineering of the KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Skeletal Biology and Engineering Research Center, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.

Regenerative cell-based implants using periosteum-derived stem cells were developed for the treatment of large 3 cm fresh and 4.5 centimeter biological compromised bone gaps in a tibial sheep model and compared with an acellular ceramic-collagen void filler. It was hypothesized that the latter is insufficient to heal large skeletal defects due to reduced endogenous biological potency. To this purpose a comparison was made between the ceramic dicalciumphosphate scaffold (CopiOs®) as such, the same ceramic coated with clinical grade Bone Morphogenetic Protein 2 and 6 (BMP) only or a BMP coated cell-seeded combination product. These implants were evaluated in 2 sheep models, a fresh 3 cm critical size tibial defect and a 4.5 cm biologically exhausted tibial defect. For the groups in which growth factors were applied, BMP-6 was chosen at a dose of 344 μg for 3 cm and 1.500 μg or 3.800 μg for 4.5 cm defects. An additional group in the 4.5 cm defect was tested using BMP-2 in a dose of 1.500 μg. For all the cell based implants autologous periosteum-derived cells were used which were cultured in monolayer during 6 weeks. For the fresh defect 408 million cells and for the biologically exhausted tibial defect 612 million cells were drop-seeded on the BMP coated scaffolds. Bone healing was studied during 16 weeks postimplantation, using standard radiographs. While fresh defects responded to all treatments, regardless the use of cells, the biologically hampered defects responded in half of the cases and only if the BMP-cell combination product was used, supporting the concept that cell-based therapies may become attractive in treating defects with a compromised biological status.
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http://dx.doi.org/10.1016/j.bone.2020.115511DOI Listing
September 2020

Recombinant Human BMP6 Applied Within Autologous Blood Coagulum Accelerates Bone Healing: Randomized Controlled Trial in High Tibial Osteotomy Patients.

J Bone Miner Res 2020 10 2;35(10):1893-1903. Epub 2020 Jul 2.

Department of Orthopedics and Trauma Surgery, Medical University of Vienna, Vienna, Austria.

Bone morphogenetic proteins (BMPs) are potent osteogenic proteins that induce new bone formation in vivo. However, their effect on bone healing in the trabecular bone surfaces remains challenging. We evaluated the safety and efficacy of recombinant human BMP6 (rhBMP6) applied within an autologous blood coagulum (ABC) in a surgically created wedge defect of the proximal tibia in patients undergoing high tibial osteotomy (HTO) for varus deformity and medial osteoarthritis of the knee. We enrolled 20 HTO patients in a randomized, placebo-controlled, double-blinded phase I/II clinical trial. RhBMP6/ABC (1.0 mg/10 mL ABC prepared from peripheral blood) or placebo (10 mL ABC containing excipients) was administered into the tibial wedge defects. Patients were followed for 0 to 24 months by clinical examination (safety) and computed tomography (CT) and serial radiographic analyses (efficacy). The results show that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 20 patients at 14 weeks after implantation. During the 24 months of follow-up, there were no serious adverse reactions recorded. The CT scans from defects of patients treated with rhBMP6/ABC showed an accelerated bone healing compared with placebo at 9 weeks (47.8 ± 24.1 versus 22.2 ± 12.3 mg/cm ; p = 0.008) and at 14 weeks (89.7 ± 29.1 versus 53.6 ± 21.9 mg/cm ; p = 0.006) follow-up. Radiographic analyses at weeks 6 and 24 and months 12 and 24 suggested the advanced bone formation and remodeling in rhBMP6/ABC-treated patients. In conclusion, we show that rhBMP6/ABC at a dose of 100 μg/mL accelerated bone healing in patients undergoing HTO without serious adverse events and with a good tolerability compared with placebo alone. Overall, for the first time, a BMP-based osteogenic implant was examined against a placebo for bone healing efficacy in the trabecular bone surface, using an objective bone mineral density measurement system. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689741PMC
October 2020

Autologous blood coagulum containing rhBMP6 induces new bone formation to promote anterior lumbar interbody fusion (ALIF) and posterolateral lumbar fusion (PLF) of spine in sheep.

Bone 2020 09 22;138:115448. Epub 2020 May 22.

Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, University of Zagreb School of Medicine, 10000 Zagreb, Croatia. Electronic address:

In the present study, we evaluated an autologous bone graft substitute (ABGS) composed of recombinant human BMP6 (rhBMP6) dispersed within autologous blood coagulum (ABC) used as a physiological carrier for new bone formation in spine fusion sheep models. The application of ABGS included cervical cage for use in the anterior lumbar interbody fusion (ALIF), while for the posterolateral lumbar fusion (PLF) sheep model allograft devitalized bone particles (ALLO) were applied with and without use of instrumentation. In the ALIF model, ABGS (rhBMP6/ABC/cage) implants fused significantly when placed in between the L4-L5 vertebrae as compared to control (ABC/cage) which appears to have a fibrocartilaginous gap, as examined by histology and micro CT analysis at 16 weeks following surgery. In the PLF model, ABGS implants with or without ALLO showed a complete fusion when placed ectopically in the gutter bilaterally between two decorticated L4-L5 transverse processes at a success rate of 88% without instrumentation and at 80% with instrumentation; however the bone volume was 50% lower in the instrumentation group than without, as examined by histology, radiographs, micro CT analyses and biomechanical testing at 27 weeks following surgery. The newly formed bone was uniform within ABGS implants resulting in a biomechanically competent and histologically qualified fusion with an optimum dose in the range of 100 μg rhBMP6 per mL ABC, while in the implants that contained ALLO, the mineralized bone particles were substituted by the newly formed remodeling bone via creeping substitution. These findings demonstrate for the first time that ABGS (rhBMP6/ABC) without and with ALLO particles induced a robust bone formation with a successful fusion in sheep models of ALIF and PLF, and that autologous blood coagulum (ABC) can serve as a preferred physiological native carrier to induce new bone at low doses of rhBMP6 and to achieve a successful spinal fusion.
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http://dx.doi.org/10.1016/j.bone.2020.115448DOI Listing
September 2020

Copresentation of BMP-6 and RGD Ligands Enhances Cell Adhesion and BMP-Mediated Signaling.

Cells 2019 12 15;8(12). Epub 2019 Dec 15.

Department of Cellular Biophysics, Max Planck Institute for Medical Research, Jahnstr. 29, 69120 Heidelberg, Germany.

We report on the covalent immobilization of bone morphogenetic protein 6 (BMP-6) and its co-presentation with integrin ligands on a nanopatterned platform to study cell adhesion and signaling responses which regulate the transdifferentiation of myoblasts into osteogenic cells. To immobilize BMP-6, the heterobifunctional linker MU-NHS is coupled to amine residues of the growth factor; this prevents its internalization while ensuring that its biological activity is maintained. Additionally, to allow cells to adhere to such platform and study signaling events arising from the contact to the surface, we used click-chemistry to immobilize cyclic-RGD carrying an azido group reacting with PEG-alkyne spacers via copper-catalyzed 1,3-dipolar cycloaddition. We show that the copresentation of BMP-6 and RGD favors focal adhesion formation and promotes Smad 1/5/8 phosphorylation. When presented in low amounts, BMP-6 added to culture media of cells adhering to the RGD ligands is less effective than BMP-6 immobilized on the surfaces in inducing Smad complex activation and in inhibiting myotube formation. Our results suggest that a local control of ligand density and cell signaling is crucial for modulating cell response.
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http://dx.doi.org/10.3390/cells8121646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953040PMC
December 2019

Autologous blood coagulum is a physiological carrier for BMP6 to induce new bone formation and promote posterolateral lumbar spine fusion in rabbits.

J Tissue Eng Regen Med 2020 01 10;14(1):147-159. Epub 2019 Nov 10.

Department of Orthopedic Surgery, Washington University, St. Louis, MO.

In the present study, we describe autologous blood coagulum (ABC) as a physiological carrier for BMP6 to induce new bone formation. Recombinant human BMP6 (rhBMP6), dispersed within ABC and formed as an autologous bone graft substitute (ABGS), was evaluated either with or without allograft bone particles (ALLO) in rat subcutaneous implants and in a posterolateral lumbar fusion (PLF) model in rabbits. ABGS induced endochondral bone differentiation in rat subcutaneous implants. Coating ALLO by ABC significantly decreased the formation of multinucleated foreign body giant cells (FBGCs) in implants, as compared with ALLO alone. However, addition of rhBMP6 to ABC/ALLO induced a robust endochondral bone formation with little or no FBGCs in the implant. In rabbit PLF model, ABGS induced new bone formation uniformly within the implant resulting in a complete fusion when placed between two lumbar transverse processes in the posterolateral gutter with an optimum dose of 100-μg rhBMP6 per ml of ABC. ABGS containing ALLO also resulted in a fusion where the ALLO was replaced by the newly formed bone via creeping substitution. Our findings demonstrate for the first time that rhBMP6, with ABC as a carrier, induced a robust bone formation with a complete spinal fusion in a rabbit PLF model. RhBMP6 was effective at low doses with ABC serving as a physiological substratum providing a permissive environment by protecting against foreign body reaction elicited by ALLO.
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http://dx.doi.org/10.1002/term.2981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027565PMC
January 2020

Analysis and quantification of bone healing after open wedge high tibial osteotomy.

Wien Klin Wochenschr 2019 Dec 9;131(23-24):587-598. Epub 2019 Sep 9.

Department for Orthopedics and Trauma-Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: The aim of this study was to analyze radiographic imaging techniques and to quantify bone ossification in the osteotomy gap after high tibial osteotomy.

Material And Methods: Study phase 1: high tibial osteotomy was performed on six lower extremities of human body donors and experimental X‑rays and computed tomography (CT) scans were applied. Different techniques were evaluated by three specialists for best representation of the osteotomy gap. Study phase 2: optimized radiological techniques were used for follow-up on 12 patients. The radiographs were examined by 3 specialists measuring 10 different parameters. The CT scans were analyzed with semiautomatic computer software for quantification of bone ossification.

Results: The osteotomy gap was best represented in 30° of flexion in the knee and 20° internal rotation of the leg. There were significant changes of the medial width over time (p < 0.019) as well as of the length of fused osteotomy, the Schröter score, sclerosis, trabecular structure and zone area measurements. Sclerosis, medial width of the osteotomy and area measurements were detected as reproducible parameters. Bone mineral density was calculated using CT scans, showing a significantly higher value 12 weeks postoperatively (112.5 mg/cm) than at baseline (54.6 mg/cm). The ossification of the gap was visualized by color coding.

Conclusion: Sclerosis and medial width of the osteotomy gap as well as area measurements were determined as reproducible parameters for evaluation of bone healing. Quantification of bone ossification can be calculated with CT scans using a semiautomatic computer program and should be used for research in bone healing.
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http://dx.doi.org/10.1007/s00508-019-01541-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908562PMC
December 2019

Unopposed estrogen and endometrial cancer: association or causation?

Croat Med J 2019 08;60(4):389

Slobodan Vukičević, Laboratory for Mineralized Tissues, Center of Excellence for Reproductive and Regenerative Medicine, University of Zagreb School of Medicine, Zagreb, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734582PMC
August 2019

Recombinant Human Bone Morphogenetic Protein 6 Delivered Within Autologous Blood Coagulum Restores Critical Size Segmental Defects of Ulna in Rabbits.

JBMR Plus 2019 May 5;3(5):e10085. Epub 2018 Nov 5.

Laboratory for Mineralized Tissues School of Medicine University of Zagreb Zagreb Croatia.

BMP2 and BMP7, which use bovine Achilles tendon-derived absorbable collagen sponge and bovine bone collagen as scaffold, respectively, have been approved as bone graft substitutes for orthopedic and dental indications. Here, we describe an osteoinductive autologous bone graft substitute (ABGS) that contains recombinant human BMP6 (rhBMP6) dispersed within autologous blood coagulum (ABC) scaffold. The ABGS is created as an injectable or implantable coagulum gel with rhBMP6 binding tightly to plasma proteins within fibrin meshwork, as examined by dot-blot assays, and is released slowly as an intact protein over 6 to 8 days, as assessed by ELISA. The biological activity of ABGS was examined in vivo in rats () and rabbits (). In a rat subcutaneous implant assay, ABGS induced endochondral bone formation, as observed by histology and micro-CT analyses. In the rabbit ulna segmental defect model, a reproducible and robust bone formation with complete bridging and restoration of the defect was observed, which is dose dependent, as determined by radiographs, micro-CT, and histological analyses. In ABGS, ABC scaffold provides a permissive environment for bone induction and contributes to the use of lower doses of rhBMP6 compared with BMP7 in bovine bone collagen as scaffold. The newly formed bone undergoes remodeling and establishes cortices uniformly that is restricted to implant site by bridging with host bone. In summary, ABC carrier containing rhBMP6 may serve as an osteoinductive autologous bone graft substitute for several orthopedic applications that include delayed and nonunion fractures, anterior and posterior lumbar interbody fusion, trauma, and nonunions associated with neurofibromatosis type I.
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http://dx.doi.org/10.1002/jbm4.10085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524675PMC
May 2019

Is ceramics an appropriate bone morphogenetic protein delivery system for clinical use?

Int Orthop 2019 05 15;43(5):1275-1276. Epub 2019 Mar 15.

Department of Orthopaedic Surgery, School of Medicine University of Zagreb, 10000, Zagreb, Croatia.

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http://dx.doi.org/10.1007/s00264-019-04322-0DOI Listing
May 2019

A novel role of bone morphogenetic protein 6 (BMP6) in glucose homeostasis.

Acta Diabetol 2019 Mar 11;56(3):365-371. Epub 2018 Dec 11.

Laboratory of Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, Salata 11, Zagreb, Croatia.

Aims: Bone morphogenetic proteins (BMPs) are involved in the development and homeostasis of multiple organs and tissues. There has been a significant focus on understanding the role of BMPs in pancreatic β-cell dysfunction associated with type 2 diabetes (T2D). Our objective was to investigate the relationship between BMP6 and glucose homeostasis.

Methods: Ob/ob mice were treated with BMP6 for 6 days and analyzed for insulin release, body weight, lipid parameters and glucose tolerance. Quantitative real-time PCR, chromatin immunoprecipitation and glucose output assays were used to assess BMP6 effect on gluconeogenesis in rat hepatoma H4IIE cells. Specificity of BMP6 receptors was characterized by the utilization of various receptor Fc fusion proteins in luciferase reporter gene and glucose output assays in INS1 and H4IIE cells.

Results: Treatment of ob/ob mice with BMP6 for 6 days resulted in a reduction of circulating glucose and lipid levels, followed by a significantly elevated plasma insulin level in a dose-dependent manner. In addition, BMP6 improved the glucose excursion during an oral glucose tolerance test, lowering the total glycemic response by 21%. In rat H4IIE hepatoma cells, BMP6 inhibited gluconeogenesis and glucose output via downregulation the PepCK expression. Moreover, BMP6 inhibited glucose production regardless of the presence of cAMP, antagonizing its glycogenolytic effect. BMP6 acted on pancreatic and liver cells utilizing Alk3, Alk6 and ActRIIA serine/threonine kinase receptors.

Conclusions: Collectively, we demonstrate that BMP6 improves glycaemia in T2D mice and regulates glucose metabolism in hepatocytes representing an exciting prospect for future treatments of diabetes.
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http://dx.doi.org/10.1007/s00592-018-1265-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394697PMC
March 2019

Prognostic significance of bone morphogenetic protein 6 (BMP6) expression, clinical and pathological factors in clinically node-negative oral squamous cell carcinoma (OSCC).

J Craniomaxillofac Surg 2019 Jan 10;47(1):80-86. Epub 2018 Nov 10.

University of Zagreb School of Medicine, Department of Maxillofacial Surgery, University Hospital Dubrava, Avenue Gojko Susak 6, 10000, Zagreb, Croatia. Electronic address:

Bone morphogenetic protein 6 (BMP6) has unique properties regarding structure and function in supporting bone formation during development and adult life. Despite its known role in various malignant tumors, the prognostic significance of BMP6 expression in oral squamous cell carcinoma (OSCC) remains unknown. The aim of the study was to investigate immunohistochemical expression of BMP6 in OSCC in correlation with clinical and pathological parameters, disease recurrence and survival. In addition, we investigated other parameters in order to identify prognosticators of neck metastases and final outcome. The study included 120 patients with clinically T1-3N0 OSCC who were primarily surgically treated between 2003 and 2008. There were 99 (82.5%) male and 21 (17.5%) female patients. The five-year disease-specific survival for the whole cohort was 79.7%. Tumors smaller than 2 cm in diameter showed higher incidence of strong BMP6 expression. No statistical correlation was observed between other clinico-pathological factors and BMP6 expression. Expression of BMP6 was not associated with disease recurrence and survival. BMP6 may not serve as prognosticator of final outcome or recurrence in clinically node-negative OSCC subjects. In multivariate analysis predictors of poorer survival were positive surgical margin, moderate tumor cell differentiation and pathological involvement of levels IV and/or V.
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http://dx.doi.org/10.1016/j.jcms.2018.10.003DOI Listing
January 2019

Antiviral activity of bone morphogenetic proteins and activins.

Nat Microbiol 2019 02 3;4(2):339-351. Epub 2018 Dec 3.

MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Understanding the control of viral infections is of broad importance. Chronic hepatitis C virus (HCV) infection causes decreased expression of the iron hormone hepcidin, which is regulated by hepatic bone morphogenetic protein (BMP)/SMAD signalling. We found that HCV infection and the BMP/SMAD pathway are mutually antagonistic. HCV blunted induction of hepcidin expression by BMP6, probably via tumour necrosis factor (TNF)-mediated downregulation of the BMP co-receptor haemojuvelin. In HCV-infected patients, disruption of the BMP6/hepcidin axis and genetic variation associated with the BMP/SMAD pathway predicted the outcome of infection, suggesting that BMP/SMAD activity influences antiviral immunity. Correspondingly, BMP6 regulated a gene repertoire reminiscent of type I interferon (IFN) signalling, including upregulating interferon regulatory factors (IRFs) and downregulating an inhibitor of IFN signalling, USP18. Moreover, in BMP-stimulated cells, SMAD1 occupied loci across the genome, similar to those bound by IRF1 in IFN-stimulated cells. Functionally, BMP6 enhanced the transcriptional and antiviral response to IFN, but BMP6 and related activin proteins also potently blocked HCV replication independently of IFN. Furthermore, BMP6 and activin A suppressed growth of HBV in cell culture, and activin A inhibited Zika virus replication alone and in combination with IFN. The data establish an unappreciated important role for BMPs and activins in cellular antiviral immunity, which acts independently of, and modulates, IFN.
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http://dx.doi.org/10.1038/s41564-018-0301-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590058PMC
February 2019

Bone morphogenetic proteins in fracture repair.

Int Orthop 2018 11 15;42(11):2619-2626. Epub 2018 Sep 15.

Center for Translational and Clinical Research, Laboratory for Mineralized Tissues, University of Zagreb School of Medicine, Salata 11, Zagreb, Croatia.

Bone fractures represent a significant medical morbidity among aged population with osteoporosis. Bone morphogenetic proteins (BMPs) are suggested to have therapeutic potential to enhance fracture healing in such patients. Though BMP-mediated fracture healing has been well-documented in preclinical models, there has been no clinical study that demonstrated unequivocally that indeed a BMP when presented with an appropriate scaffold could provide basis for robust outcome for delayed or non-union diaphyseal bone fractures. This review presents a comprehensive insight towards the existing knowledge on the role of BMP signaling in bone formation and maintenance. Also therapeutic options based on BMP biology are discussed.A novel osteoinductive autologous bone graft substitute (ABGS) aimed to accelerate bone regeneration was developed and is currently being tested in the clinical setting. It comprises of a biologically compatible autologous carrier made from the patient's peripheral blood (autologous blood coagulum, ABC) and of rhBMP6 as an active ingredient. Such formulation circumvents the use of animal-derived materials, significantly limits inflammatory processes common in commercial bone devices and renders the carrier flexible, malleable, and injectable ensuring the ease of use. The ongoing clinical trials result will provide more detailed insights into the safety, tolerability, pharmacokinetics, and bone healing effects in humans and potentially provide novel and safe therapeutic options for bone repair.
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http://dx.doi.org/10.1007/s00264-018-4153-yDOI Listing
November 2018

Science communication to the public.

Croat Med J 2018 04;59(2):43-45

Slobodan Vukičević, Laboratory of Mineralized Tissues, Scientific Center of Excellence for Reproductive and Regenerative Medicine, University of Zagreb School of Medicine, Zagreb, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941289PMC
http://dx.doi.org/10.3325/cmj.2018.59.43DOI Listing
April 2018

Systemic inhibition of BMP1-3 decreases progression of CCl-induced liver fibrosis in rats.

Growth Factors 2017 12 27;35(6):201-215. Epub 2018 Feb 27.

a Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine , University of Zagreb, Scientific Center of Excellence for Reproductive and Regenerative Medicine , Zagreb , Croatia.

Liver fibrosis is a progressive pathological process resulting in an accumulation of excess extracellular matrix proteins. We discovered that bone morphogenetic protein 1-3 (BMP1-3), an isoform of the metalloproteinase Bmp1 gene, circulates in the plasma of healthy volunteers and its neutralization decreases the progression of chronic kidney disease in 5/6 nephrectomized rats. Here, we investigated the potential role of BMP1-3 in a chronic liver disease. Rats with carbon tetrachloride (CCl)-induced liver fibrosis were treated with monoclonal anti-BMP1-3 antibodies. Treatment with anti-BMP1-3 antibodies dose-dependently lowered the amount of collagen type I, downregulated the expression of Tgfb1, Itgb6, Col1a1, and Acta2 and upregulated the expression of Ctgf, Itgb1, and Dcn. Mehanistically, BMP1-3 inhibition decreased the plasma levels of transforming growth factor beta 1(TGFβ1) by prevention of its activation and lowered the prodecorin production further suppressing the TGFβ1 profibrotic effect. Our results suggest that BMP1-3 inhibitors have significant potential for decreasing the progression of fibrosis in liver cirrhosis.
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http://dx.doi.org/10.1080/08977194.2018.1428966DOI Listing
December 2017

Clinical need for bone morphogenetic proteins.

Int Orthop 2017 11 29;41(11):2415-2416. Epub 2017 Jun 29.

Department of Orthopaedic Surgery, School of Medicine University of Zagreb, 10000, Zagreb, Croatia.

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http://dx.doi.org/10.1007/s00264-017-3550-yDOI Listing
November 2017

Marshall R. Urist and the discovery of bone morphogenetic proteins.

Int Orthop 2017 May 11;41(5):1065-1069. Epub 2017 Feb 11.

Laboratory for Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, Salata 11, 10000, Zagreb, Croatia.

Over the last 40 years International Orthopaedics has published a series of articles on bone morphogenetic proteins (BMPs) covering topics from basic research to clinical applications. This includes also work submitted from the Laboratory for Mineralized Tissues of the School of Medicine University of Zagreb. Accordingly, we felt obliged to give a short summary of Dr. Urist's life and work as our gratitude to his discovery that demineralized bone matrix (DBM) activity induces bone when implanted ectopically into the muscle or under the skin due to bone inducing proteins, named BMPs.
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http://dx.doi.org/10.1007/s00264-017-3402-9DOI Listing
May 2017

Mushroom Extracts Decrease Bone Resorption and Improve Bone Formation.

Int J Med Mushrooms 2016 ;18(7):559-69

Dr Myko San—Health from Mushrooms, Zagreb, Croatia.

Mushroom extracts have shown promising effects in the treatment of cancer and various chronic diseases. Osteoporosis is considered one of the most widespread chronic diseases, for which currently available therapies show mixed results. In this research we investigated the in vitro effects of water extracts of the culinary-medicinal mushrooms Trametes versicolor, Grifola frondosa, Lentinus edodes, and Pleurotus ostreatus on a MC3T3-E1 mouse osteoblast-like cell line, primary rat osteoblasts, and primary rat osteoclasts. In an animal osteoporosis model, rats were ovariectomized and then fed 2 mushroom blends of G. frondosa and L. edodes for 42 days. Bone loss was monitored using densitometry (dual-energy X-ray absorptiometry) and micro computed tomography. In the concentration test, mushroom extracts showed no toxic effect on MC3T3-E1 cells; a dose of 24 µg/mL showed the most proliferative effect. Mushroom extracts of T. versicolor, G. frondosa, and L. edodes inhibited osteoclast activity, whereas the extract of L. edodes increased osteoblast mineralization and the production of osteocalcin, a specific osteoblastic marker. In animals, mushroom extracts did not prevent trabecular bone loss in the long bones. However, we show for the first time that the treatment with a combination of extracts from L. edodes and G. frondosa significantly reduced trabecular bone loss at the lumbar spine. Inhibitory properties of extracts from L. edodes on osteoclasts and the promotion of osteoblasts in vitro, together with the potential to decrease lumbar spine bone loss in an animal osteoporosis model, indicate that medicinal mushroom extracts can be considered as a preventive treatment and/or a supplement to pharmacotherapy to enhance its effectiveness and ameliorate its harmful side effects.
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http://dx.doi.org/10.1615/intjmedmushrooms.v18.i7.10DOI Listing
March 2017

Constitutively Elevated Blood Serotonin Is Associated with Bone Loss and Type 2 Diabetes in Rats.

PLoS One 2016 23;11(2):e0150102. Epub 2016 Feb 23.

Laboratory of Mineralized Tissues, Center for Translational and Clinical Research, School of Medicine, University of Zagreb, Zagreb, Croatia.

Reduced peripheral serotonin (5HT) in mice lacking tryptophan hydroxylase (TPH1), the rate limiting enzyme for 5HT synthesis, was reported to be anabolic to the skeleton. However, in other studies TPH1 deletion either had no bone effect or an age dependent inhibition of osteoclastic bone resorption. The role of 5HT in bone therefore remains poorly understood. To address this issue, we used selective breeding to create rat sublines with constitutively high (high-5HT) and low (low-5HT) platelet 5HT level (PSL) and platelet 5HT uptake (PSU). High-5HT rats had decreased bone volume due to increased bone turnover characterized by increased bone formation and mineral apposition rate, increased osteoclast number and serum C-telopeptide level. Daily oral administration of the TPH1 inhibitor (LX1032) for 6 weeks reduced PSL and increased the trabecular bone volume and trabecular number of the spine and femur in high-5HT rats. High-5HT animals also developed a type 2 diabetes (T2D) phenotype with increased: plasma insulin, glucose, hemoglobin A1c, body weight, visceral fat, β-cell pancreatic islets size, serum cholesterol, and decreased muscle strength. Serum calcium accretion mediated by parathyroid hormone slightly increased, whereas treatment with 1,25(OH)2D3 decreased PSL. Insulin reduction was paralleled by a drop in PSL in high-5HT rats. In vitro, insulin and 5HT synergistically up-regulated osteoblast differentiation isolated from high-5HT rats, whereas TPH1 inhibition decreased the number of bone marrow-derived osteoclasts. These results suggest that constitutively elevated PSL is associated with bone loss and T2D via a homeostatic interplay between the peripheral 5HT, bone and insulin.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150102PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764355PMC
July 2016

Bone morphogenetic proteins in inflammation, glucose homeostasis and adipose tissue energy metabolism.

Cytokine Growth Factor Rev 2016 Feb 29;27:105-18. Epub 2015 Dec 29.

University of Zagreb School of Medicine, Center for Translational and Clinical Research, Laboratory for Mineralized Tissues, Zagreb, Croatia. Electronic address:

Bore morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)-β superfamily, a group of secreted proteins that regulate embryonic development. This review summarizes the effects of BMPs on physiological processes not exclusively linked to the musculoskeletal system. Specifically, we focus on the involvement of BMPs in inflammatory disorders, e.g. fibrosis, inflammatory bowel disease, anchylosing spondylitis, rheumatoid arthritis. Moreover, we discuss the role of BMPs in the context of vascular disorders, and explore the role of these signalling proteins in iron homeostasis (anaemia, hemochromatosis) and oxidative damage. The second and third parts of this review focus on BMPs in the development of metabolic pathologies such as type-2 diabetes mellitus and obesity. The pancreatic beta cells are the sole source of the hormone insulin and BMPs have recently been implicated in pancreas development as well as control of adult glucose homeostasis. Lastly, we review the recently recognized role of BMPs in brown adipose tissue formation and their consequences for energy expenditure and adiposity. In summary, BMPs play a pivotal role in metabolism beyond their role in skeletal homeostasis. However, increased understanding of these pleiotropic functions also highlights the necessity of tissue-specific strategies when harnessing BMP action as a therapeutic target.
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http://dx.doi.org/10.1016/j.cytogfr.2015.12.009DOI Listing
February 2016

VE-cadherin facilitates BMP-induced endothelial cell permeability and signaling.

J Cell Sci 2016 Jan 23;129(1):206-18. Epub 2015 Nov 23.

Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin 14195, Germany DFG Graduate School 1093 Berlin School of Integrative Oncology, Berlin 13353, Germany DFG Graduate School 203 Berlin-Brandenburg School for Regenerative Therapies, Berlin 13353, Germany

Several vascular disorders, such as aberrant angiogenesis, atherosclerosis and pulmonary hypertension, have been linked to dysfunctional BMP signaling. Vascular hyperpermeability via distortion of endothelial cell adherens junctions is a common feature of these diseases, but the role of BMPs in this process has not been investigated. BMP signaling is initiated by binding of ligand to, and activation of, BMP type I (BMPRI) and type II (BMPRII) receptors. Internalization of VE-cadherin as well as c-Src kinase-dependent phosphorylation have been implicated in the loosening of cell-cell contacts, thereby modulating vascular permeability. Here we demonstrate that BMP6 induces hyperpermeabilization of human endothelial cells by inducing internalization and c-Src-dependent phosphorylation of VE-cadherin. Furthermore, we show BMP-dependent physical interaction of VE-cadherin with the BMP receptor ALK2 (BMPRI) and BMPRII, resulting in stabilization of the BMP receptor complex and, thereby, the support of BMP6-Smad signaling. Our results provide first insights into the molecular mechanism of BMP-induced vascular permeability, a hallmark of various vascular diseases, and provide the basis for further investigations of BMPs as regulators of vascular integrity, both under physiological and pathophysiological conditions.
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http://dx.doi.org/10.1242/jcs.179960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732303PMC
January 2016

Soluble type III TGFβ receptor in diagnosis and follow-up of patients with breast cancer.

Growth Factors 2015 20;33(3):200-9. Epub 2015 Jul 20.

b Laboratory for Mineralized Tissues , Center for Translational and Clinical Research, School of Medicine, University of Zagreb , Croatia .

Type III transforming growth factor (TGFβ) receptor (TGFβrIII) modulates TGFβ superfamily signaling. Its tumor tissue expression is downregulated in human breast cancer. We determined (indirect ELISA) plasma levels of the soluble receptor (sTGFβrIII) in 47 women with breast cancer (AJCC stages 0-IIB) (cases) pre-surgery and over two months after the surgery, and in 36 healthy women (controls). Plasma sTBFβrIII was lower in cases than in the controls (age-adjusted difference -29.7 ng/mL, p < 0.001), and discriminated between disease and health (sensitivity and specificity 100% at 16.6 ng/mL). With adjustment for age, AJCC stage, lymph node involvement, HER2 and hormone receptor status, higher pre-surgery sTBFβrIII was associated with better progression-free survival (HR = 0.68, 95%CI 0.49-0.89, p = 0.004). An increasing trend in plasma sTBFβrIII was observed over 2 months after the surgery (0.6% increase/day, p < 0.001), consistently across the patient subsets. Data suggest a high potential of plasma sTBFβrIII as a novel diagnostic and prognostic biomarker in breast cancer.
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http://dx.doi.org/10.3109/08977194.2015.1055740DOI Listing
August 2016