Publications by authors named "Ivo Dumic-Cule"

20 Publications

  • Page 1 of 1

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

The importance of introducing artificial intelligence to the medical curriculum - assessing practitioners' perspectives.

Croat Med J 2020 Oct;61(5):457-464

Ivo Dumić-Čule, Children`s Hospital Srebrnjak, Srebrnjak 100, 10000 Zagreb, Croatia,

Aim: To assess the attitude about the importance of introducing education on artificial intelligence (AI) in medical schools' curricula among physicians whose everyday job is significantly impacted by AI.

Methods: An anonymous questionnaire was distributed at the national level in Croatia among radiologists and radiology residents practicing in primary, secondary, and tertiary health care institutions, both in the private and the public sectors. The overall response rate was 45% (144 of 321).

Results: A large majority of participants - 89.6% (95% Agresti-Coull confidence interval 0.83-0.94) agreed on the need for education on AI to be included in medical curricula. Answers revealed a very high support across age groups and regardless of subspecialty area. A slightly higher support was present among physicians working in university hospitals compared with those in primary care centers, and among radiology residents compared with radiologists - but these estimated differences are uncertain, and the support levels were clearly high across the considered variables.

Conclusion: Since medical students have previously been shown to support introducing education on AI, a growing literature argues the same for reasons here reviewed, and physicians practicing a highly relevant area (radiology) overwhelmingly agree, we conclude that medical schools should indeed take steps to keep pace with technological progress in medicine by including education on AI in their curricula, be it as part of existing or new courses.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684542PMC
October 2020

Importance of shear-wave elastography in prediction of Achilles tendon rupture.

Int Orthop 2020 Jun 29. Epub 2020 Jun 29.

Department of Diagnostic and Interventional Radiology, University Hospital Dubrava, Av. Gojka Suska 6, 10000, Zagreb, Croatia.

Purpose: It was demonstrated that about 6% of patients with a ruptured Achilles tendon experience the rupture of contralateral tendon in the future; the aim of this study was to estimate the risk for rupture of contralateral tendon in patients who underwent surgical reconstruction of ruptured Achilles tendon by using subjective questionnaires and shear-wave elastography.

Methods: Twenty-four patients who underwent surgical repair of the ruptured Achilles tendon and twelve age-matched healthy controls were examined with ultrasound SWE. Functional outcomes were assessed with American Orthopedic Foot and Ankle Society (AOFAS) scoring system and subjective rating system which we introduced and validated.

Results: The elasticity of injured tendon was markedly decreased (by 42%) compared to the contralateral tendon of the patient, as expected. Both AOFAS score and our novel subjective assessment scale positively correlate with ultrasound SWE values in ruptured Achilles tendons. The elasticity of contralateral Achilles tendons in patients was 23% lower than among healthy individuals.

Conclusion: Irrespective of the lack of difference in the subjective feeling assessed by AOFAS, the contralateral tendon in the patients with reconstructed Achilles tendon has significantly lower stiffness than healthy individuals. Therefore, contralateral tendons in patients who suffered from rupture are more prone to future ruptures.
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http://dx.doi.org/10.1007/s00264-020-04670-2DOI Listing
June 2020

PALMARIS LONGUS ABSENT IN ONE IDENTICAL TWIN: A CASE REPORT.

Acta Clin Croat 2018 Dec;57(4):772-775

1Department of Anatomy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia; 2Laboratory for Mineralized Tissues, School of Medicine, University of Zagreb, Zagreb, Croatia; 3Department of Diagnostic and Interventional Radiology, Dubrava University Hospital, Zagreb, Croatia.

- Palmaris longus is a very variable muscle in the human body, but it is often used as an applicable tendon graft. We report on differences between one pair of identical twins regarding the existence of the palmaris longus, which were detected accidentally during examination of the presence/absence of this muscle in Caucasian population. In one of the twins, the palmaris longus was present at both forearms, while the other twin was lacking this muscle at both forearms. On search of the available literature, we found no articles about distinctions in the presence or absence of the palmaris longus in twins.
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http://dx.doi.org/10.20471/acc.2018.57.04.21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544091PMC
December 2018

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

Magnitude dependent discordance in liver stiffness measurements using elastography point quantification with transient elastography as the reference test.

Eur Radiol 2019 May 28;29(5):2448-2456. Epub 2018 Nov 28.

Department of Gastroenterology, Hepatology and Clinical Nutrition; Department of Medicine, University Hospital Dubrava, University of Zagreb School of Medicine and Faculty of Pharmacy and Biochemistry, Avenija Gojka Suska 6, 10000, Zagreb, Croatia.

Objectives: To investigate diagnostic performance of point shear wave elastography by elastography point quantification (ElastPQ) for non-invasive assessment of liver fibrosis in patients with chronic liver diseases (CLD).

Methods: Liver stiffness measurement (LSM) by transient elastography (TE) and ElastPQ was performed in patients with CLD and healthy volunteers. The stage of liver fibrosis was defined by TE which served as the reference. We compared two methods by using correlation, area under the receiver operating characteristics curve (AUC) analysis, Bland and Altman plot and Passing-Bablok regression.

Results: A total of 185 subjects (20 healthy volunteers and 165 patients with CLD (128 non-alcoholic fatty liver disease), 83 (44.9%) females, median age 53 years, BMI 27.3 kg/m) were evaluated. There were 24.3%, 13.5% and 11.4% patients in ≥ F2, ≥ F3 and F4 stage, respectively. The best performing cutoff LSM values by ElastPQ were 5.5 kPa for F ≥ 2 (AUC = 0.96), 8.1 kPa for F ≥ 3 (AUC = 0.98) and 9.9 kPa for F4 (AUC = 0.98). Mean (SD) difference between TE and ElastPQ measurements was 0.98 (3.27) kPa (95% CI 0.51-1.45, range 4.99-21.60 kPa). Two methods correlated significantly (r = 0.86; p < 0.001), yet Bland and Altman plot demonstrated difference between measurements, especially with TE values > 10 kPa. Passing and Bablok regression analysis yielded significant constant and proportional difference between ElastPQ and TE.

Conclusion: ElastPQ is reliable method for assessment of liver fibrosis but LSM values are not interchangeable with TE, especially above 10 kPa. Diagnostic performance of ElastPQ for sub-classification of patients with compensated advanced chronic liver disease should therefore be furtherly investigated.

Key Points: • ElastPQ appears to be reliable method for assessment of liver fibrosis, with data presented here mostly applicable to NAFLD. • LSM values produced by TE and ElastPQ are NOT interchangeable-in values < 10 kPa, they are similar, but in values > 10 kPa, they appear to be increasingly and significantly different. • Diagnostic performance of ElastPQ for sub-classification of patients with compensated advanced chronic liver disease should be furtherly investigated.
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http://dx.doi.org/10.1007/s00330-018-5831-2DOI Listing
May 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

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

Association of Generalized Psoriasis and Mixed Glomerulonephritis in a 10-year-old Girl.

Acta Dermatovenerol Croat 2017 Jul;25(2):142-144

Prof. Danko Milošević, MD, PhD, Department of Pediatric Nephrology, Dialysis and Transplantation, University Hospital Center Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia;

Generalized psoriasis and renal function disorder were previously described in sporadic adult cases, revealing a new entity - psoriatic nephropathy. So far there have been only two cases describing this association in children. We present and discuss a case of 10-year-old girl with the unique biopsy findings of double glomerulonephritis associated with the simultaneous onset of generalized psoriasis.
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July 2017

Current Therapeutic Approach to Hypertrophic Scars.

Front Med (Lausanne) 2017 20;4:83. Epub 2017 Jun 20.

Department of Dermatology and Venereology, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia.

Abnormal scarring and its accompanying esthetic, functional, and psychological sequelae still pose significant challe nges. To date, there is no satisfactory prevention or treatment option for hypertrophic scars (HSs), which is mostly due to not completely comprehending the mechanisms underlying their formation. That is why the apprehension of regular and controlled physiological processes of scar formation is of utmost importance when facing hypertrophic scarring, its pathophysiology, prevention, and therapeutic approach. When treating HSs and choosing the best treatment and prevention modality, physicians can choose from a plethora of therapeutic options and many commercially available products, among which currently there is no efficient option that can successfully overcome impaired skin healing. This article reviews current therapeutic approach and emerging therapeutic strategies for the management of HSs, which should be individualized, based on an evaluation of the scar itself, patients' expectations, and practical, evidence-based guidelines. Clinicians are encouraged to combine various prevention and treatment modalities where combination therapy that includes steroid injections, 5-fluorouracil, and pulsed-dye laser seems to be the most effective. On the other hand, the current therapeutic options are usually empirical and their results are unreliable and unpredictable. Therefore, there is an unmet need for an effective, targeted therapy and prevention, which would be based on an action or a modulation of a particular factor with clarified mechanism of action that has a beneficial effect on wound healing. As the extracellular matrix has a crucial role in cellular and extracellular events that lead to pathological scarring, targeting its components mostly by regulating bone morphogenetic proteins may throw up new therapeutic approach for reduction or prevention of HSs with functionally and cosmetically acceptable outcome.
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http://dx.doi.org/10.3389/fmed.2017.00083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476971PMC
June 2017

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

Sphenoid sinus types, dimensions and relationship with surrounding structures.

Ann Anat 2016 Jan 20;203:69-76. Epub 2015 Mar 20.

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

The human sphenoid sinus is an extremely variable cavity and an important landmark in hypophyseal surgery. The aim of this study was to investigate the relationship between the sphenoid sinus type, size, extent of pneumatization and occurrence of protrusions of the adjacent neurovascular structures. A total of 51 randomly selected skulls (≥20 years of age, 33 male; 102 sinuses) were analyzed using cone beam computed tomography to estimate pneumatization extension beyond the body of the sphenoid (planum sphenoidale, pterygoid process, greater wings, clivus, dorsum sellae) and protrusions of the maxillary, mandibular, optic or pterygoid nerve or the internal carotid artery. Difference in pneumatization type between the left and the right-sided sinus was observed in 45% of the skulls. Conchal pneumatization was registered in 2%, presellar in 24%, sellar in 41% and postsellar in 33% of total sinuses. Presellar sinuses frequently pneumatized planum sphenoidale and sporadically other structures, and were characterized by sporadic optic nerve protrusions. Sellar and particularly postsellar sinuses were characterized by simultaneous pneumatization extensions and neurovascular protrusions. In the case of postsellar-type sinuses, the probability of these multiple interactions was not affected by their actual size, while it increased with the increasing sinus dimensions in the case of sellar-type sinuses. A more detailed analysis indicated that increasing sinus height, length or width increased the probability of interactions and pneumatization of particular surrounding structures. Data suggest that the sphenoid sinus pneumatization type and dimensions might be used to estimate the risks of iatrogenic injury during transsphenoidal surgical procedures.
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http://dx.doi.org/10.1016/j.aanat.2015.02.013DOI Listing
January 2016

Biological aspects of segmental bone defects management.

Int Orthop 2015 May 17;39(5):1005-11. Epub 2015 Mar 17.

Laboratory for Mineralised Tissues, Centre for Translational and Clinical Research, School of Medicine, University of Zagreb, Šalata 11, Zagreb, 10000, HR, Croatia.

Segmental bone defect management is among the most demanding issues in orthopaedics and there is a great medical need for establishing an appropriate treatment option. Tissue transfer, including bone autografts or free flaps, depending on the size of the bone deficiency, is currently the "gold standard" for treatment of such defects. Osteogenic cells in combination with adequate growth factors and a suitable scaffold, from the aspect of osteoinductivity, osteoconductivity and mechanical stability, are mandatory to successfully restore a bone defect as determined in the "diamond concept". Our current knowledge on this topic is limited and mostly based on retrospective studies, case reports and a few small randomised clinical trials due to the lack of large and accurately designed randomised clinical trials using novel approaches to regenerative orthopaedics. However, preclinical research on different animal models for critical size defects is abundant, showing emerging candidate cells and cytokines for defect rebridgement. In this article we provide an overview on existing clinical studies and promising preclinical experiments that utilised osteogenic cells, growth factors and biomaterials, as well as their combination for repair of segmental bone defects.
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http://dx.doi.org/10.1007/s00264-015-2728-4DOI Listing
May 2015

Possible target for preventing fibrotic scar formation following acute myocardial infarction.

Med Hypotheses 2014 Dec 2;83(6):656-8. Epub 2014 Oct 2.

Laboratory for Mineralized Tissue, Department of Anatomy, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia.

Bone morphogenetic protein 1 (BMP1) was originally isolated from bone with other BMPs due to its affinity for heparin. While all other BMPs are members of the Transforming Growth Factor β (TGFβ) superfamily of growth factors, BMP1 is not an authentic member of the BMP protein family. Together with mammalian Tolloid Like protein 1 (mTLL-1) and mTLL-2, BMP1 comprise a small group of zinc- and calcium-dependent proteinases. Acute myocardial infarction (AMI) is the leading cause of death in developed countries which accounts for 13% of deaths worldwide. It was recently shown that inhibition of BMP1-3 reduces progression of fibrosis in chronic kidney disease and suggested that BMP1-3 is an important molecule for fibrogenesis. We hypothesize that inhibition of BMP1-3 represents future of therapeutic interventions in the heart tissue fibrosis following AMI. This novel approach aims to acquire the first candidate specific treatment for recuperating the heart function in patients with AMI.
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http://dx.doi.org/10.1016/j.mehy.2014.09.011DOI Listing
December 2014

Systemically available bone morphogenetic protein two and seven affect bone metabolism.

Int Orthop 2014 Sep 17;38(9):1979-85. Epub 2014 Jul 17.

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

Purpose: Bone morphogenetic protein (BMP)-2 and -7 are used in patients with long-bone fractures, nonunions and spinal fusions. It is unknown whether their potential systemic bioavailability following local bone administration might affect skeletal metabolism. To answer this question, we examined effects of systemically administered BMP-2 and -7 on bone in a newly developed rat model with a low level of calciotropic hormones.

Methods: Removal of thyroid and parathyroid glands (TPTx) in rats resulted in a decreased level of calciotropic hormones and subsequent bone loss assessed by micro computed tomography (micro-CT) and measurement of serum bone formation and resorption markers, including osteocalcin, C-telopeptide, osteoprotegerin and receptor activator of nuclear factor kappa-B ligand. Results were complemented with in vitro studies on osteoblast and osteoclast activity by both BMP-2 and -7. The doses used were calculated from published pharmacodynamic studies and bioavailability results from preclinical BMP-2 and -7 studies.

Results: TPTx resulted in bone loss, which was restored by systemic administration of 10-70 μg/kg of BMP-2 and 10-250 μg/kg of BMP-7. BMP-2 showed a higher capacity for enhancing trabecular microarchitecture, whereas BMP-7 augmented trabecular thickness. In vitro experiments revealed that BMP-2 and -7 when uncoupled increased the number and activity of both osteoblasts and osteoclasts.

Conclusions: Surprisingly, both BMP-2 and -7 showed an increased bone volume in an in vivo environment of low calciotropic hormones. Locally administered BMP-2 and -7 from bone devices might become partially available in circulation but will not mediate systemic bone loss.
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http://dx.doi.org/10.1007/s00264-014-2425-8DOI Listing
September 2014

The rational use of animal models in the evaluation of novel bone regenerative therapies.

Bone 2015 Jan 13;70:73-86. Epub 2014 Jul 13.

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

Bone has a high potential for endogenous self-repair. However, due to population aging, human diseases with impaired bone regeneration are on the rise. Current strategies to facilitate bone healing include various biomolecules, cellular therapies, biomaterials and different combinations of these. Animal models for testing novel regenerative therapies remain the gold standard in pre-clinical phases of drug discovery and development. Despite improvements in animal experimentation, excessive poorly designed animal studies with inappropriate endpoints and inaccurate conclusions are being conducted. In this review, we discuss animal models, procedures, methods and technologies used in bone repair studies with the aim to assist investigators in planning and performing scientifically sound experiments that respect the wellbeing of animals. In the process of designing an animal study for bone repair investigators should consider: skeletal characteristics of the selected animal species; a suitable animal model that mimics the intended clinical indication; an appropriate assessment plan with validated methods, markers, timing, endpoints and scoring systems; relevant dosing and statistically pre-justified sample sizes and evaluation methods; synchronization of the study with regulatory requirements and additional evaluations specific to cell-based approaches. This article is part of a Special Issue entitled "Stem Cells and Bone".
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http://dx.doi.org/10.1016/j.bone.2014.07.010DOI Listing
January 2015

Dynamics of optic canal and orbital cavity development revealed by microCT.

Surg Radiol Anat 2014 Dec 19;36(10):989-92. Epub 2014 Apr 19.

Department of Anatomy, School of Medicine, University of Zagreb, Salata 11, 10000, Zagreb, Croatia.

Purpose: Numerous studies have attempted to clarify the exact anatomy and variations of the optic canal with non-conclusive results due to its close proximity to many vulnerable structures. We sought to determine the dynamics of growth and development of these structures on fetal skulls, which will help us to better understand of gender and age-dependent variations, as well as fatal malformations.

Methods: Fifteen previously macerated fetal frontal and sphenoid bones were analyzed and the diameters of optic canal, and distance of orbit from frontomaxillary suture to frontozygomatic suture were measured using 3D reconstruction images obtained by micro-CT.

Results: Average diameter of the optic canal in 300 mm fetus was measured to be 1,546 ± 36 µm, in 400 mm fetus 2,470 ± 123 µm and in 500 mm fetus 3,757 ± 203 µm. This trend indicates a linear enlargement of optic canal during the fetal period. During the same time period, diameter of the orbit enlarges from 12,319 ± 559 µm in 300 mm fetus to 19,788 ± 736 µm in 500 mm fetus. Growth curve is significantly lower in comparison with the same curve in optic canal data. We also calculated the ratio of orbit diameter and optic canal diameter between those groups which decreased from a value of 7.9 ± 0.4 for 300 mm fetus to 5.3 ± 0.2 for 500 mm fetus.

Conclusion: Dynamics of optic canal and orbital cavity development is different in early and late fetal period. Diameters of those structures are in better correlation with the fetal length.
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http://dx.doi.org/10.1007/s00276-014-1296-4DOI Listing
December 2014

The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing.

Int Orthop 2014 Mar 19;38(3):635-47. Epub 2013 Dec 19.

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

Purpose: The purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW.

Methods: Complications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/- mice by μCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits.

Results: Clinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of osteoclasts derived from HSC, while BMP2 and BMP7 increased their number.

Conclusions: Current issues and challenges with commercial bone devices may be resolved by using novel BMP6 biocompatible device OSTEOGROW, which will be clinically tested in metaphyseal bone fractures, compartments where BMP2 and BMP7 have not been effective.
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http://dx.doi.org/10.1007/s00264-013-2201-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3936094PMC
March 2014

Potential beneficial role of sevelamer hydrochloride in diabetic retinopathy.

Med Hypotheses 2013 Apr 26;80(4):431-5. Epub 2013 Jan 26.

Eye Specialty Hospital "Svjetlost", Medical School, University of Rijeka, Croatia.

Patients with chronic kidney disease (CKD) experience co-morbid illnesses, including cardiovascular disease and retinopathy. Sevelamer hydrochloride (Renagel®); a non-calcium phosphate binder reduces coronary artery and aortic calcification as compared to calcium containing phosphate binders and additionally effects inflammatory biomarkers such as C-reactive protein (CRP), and lowers LDL cholesterol in patients with CKD. Since retinopathy is proven to be associated with increased coronary calcification, shared pathophysiological processes may contribute to both microvascular and macrovascular disease. We here suggest three different mechanisms of possible sevelamer's influence on the retinopathy: (1) by direct effect on the microvasculature through lowering CRP and LDL, involved in endothelial dysfunction and atherogenesis, (2) indirectly by attenuation of vascular calcification of aorta and carotid internal artery, it reduces ischaemia and improves circulation in the opthalmic artery and hence postponing retinopathy, (3) through hypertension by reducing atherosclerosis and calcification of carotid arteries, sevelamer decreases stiffness and intima-media wall thickness, therefore lowering blood pressure, which is well known to increase progression of diabetic retinopathy. So far no studies have yet been published on the direct influence of sevelamer on the retinopathy which we believe has good theoretical background. With its combined macrovascular and microvascular effect, sevelamer could potentially postpone and/or decrease retinopathy in diabetic patients with hypertension, and that are on hemodialysis or even predialysis patients.
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http://dx.doi.org/10.1016/j.mehy.2012.12.035DOI Listing
April 2013

Bone morphogenetic protein (BMP)1-3 enhances bone repair.

Biochem Biophys Res Commun 2011 Apr 29;408(1):25-31. Epub 2011 Mar 29.

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

Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP-1) regulate morphogenesis by processing precursors to mature functional extracellular matrix (ECM) proteins and several growth factors including TGFβ, BMP2, BMP4 and GFD8. We have recently discovered that BMP1-3 isoform of the Bmp-1 gene circulates in the human plasma and is significantly increased in patients with acute bone fracture. We hypothesized that circulating BMP1-3 might have an important role in bone repair and serve as a novel bone biomarker. When administered systemically to rats with a long bone fracture and locally to rabbits with a critical size defect of the ulna, recombinant human BMP1-3 enhanced bone healing. In contrast, neutralization of the endogenous BMP1-3 by a specific polyclonal antibody delayed the bone union. Invitro BMP1-3 increased the expression of collagen type I and osteocalcin in MC3T3-E(1) osteoblast like cells, and enhanced the formation of mineralized bone nodules from bone marrow mesenchymal stem cells. We suggest that BMP1-3 is a novel systemic regulator of bone repair.
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http://dx.doi.org/10.1016/j.bbrc.2011.03.109DOI Listing
April 2011