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Dive into the research topics where Hrvoje Cvija is active.

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Featured researches published by Hrvoje Cvija.


Journal of Dental Research | 2013

In vivo Identification of Periodontal Progenitor Cells

Hrvoje Roguljić; Brya G. Matthews; W. Yang; Hrvoje Cvija; Mina Mina; Ivo Kalajzic

The periodontal ligament contains progenitor cells; however, their identity and differentiation potential in vivo remain poorly characterized. Previous results have suggested that periodontal tissue progenitors reside in perivascular areas. Therefore, we utilized a lineage-tracing approach to identify and track periodontal progenitor cells from the perivascular region in vivo. We used an alpha-smooth muscle actin (αSMA) promoter-driven and tamoxifen-inducible Cre system (αSMACreERT2) that, in combination with a reporter mouse line (Ai9), permanently labels a cell population, termed ‘SMA9’. To trace the differentiation of SMA9-labeled cells into osteoblasts/cementoblasts, we utilized a Col2.3GFP transgene, while expression of Scleraxis-GFP was used to follow differentiation into periodontal ligament fibroblasts during normal tissue formation and remodeling following injury. In uninjured three-week-old SMA9 mice, tamoxifen labeled a small population of cells in the periodontal ligament that expanded over time, particularly in the apical region of the root. By 17 days and 7 weeks after labeling, some SMA9-labeled cells expressed markers indicating differentiation into mature lineages, including cementocytes. Following injury, SMA9 cells expanded, and differentiated into cementoblasts, osteoblasts, and periodontal ligament fibroblasts. SMA9-labeled cells represent a source of progenitors that can give rise to mature osteoblasts, cementoblasts, and fibroblasts within the periodontium.


Laboratory Investigation | 2010

Fas receptor is required for estrogen deficiency-induced bone loss in mice

Nataša Kovačić; Danka Grčević; Vedran Katavić; Ivan Krešimir Lukić; Vladimir Grubišić; Karlo Mihovilović; Hrvoje Cvija; Peter I. Croucher; Ana Marušić

Bone mass is determined by bone cell differentiation, activity, and death, which mainly occur through apoptosis. Apoptosis can be triggered by death receptor Fas (CD95), expressed on osteoblasts and osteoclasts and may be regulated by estrogen. We have previously shown that signaling through Fas inhibits osteoblast differentiation. In this study we analyzed Fas as a possible mediator of bone loss induced by estrogen withdrawal. At 4 weeks after ovariectomy (OVX), Fas gene expression was greater in osteoblasts and lower in osteoclasts in ovariectomized C57BL/6J (wild type (wt)) mice compared with sham-operated animals. OVX was unable to induce bone loss in mice with a gene knockout for Fas (Fas –/– mice). The number of osteoclasts increased in wt mice after OVX, whereas it remained unchanged in Fas –/– mice. OVX induced greater stimulation of osteoblastogenesis in Fas –/– than in wt mice, with higher expression of osteoblast-specific genes. Direct effects on bone cell differentiation and apoptosis in vivo were confirmed in vitro, in which addition of estradiol decreased Fas expression and partially abrogated the apoptotic and differentiation-inhibitory effect of Fas in osteoblast lineage cells, while having no effect on Fas-induced apoptosis in osteoclast lineage cells. In conclusion, the Fas receptor has an important role in the pathogenesis of postmenopausal osteoporosis by mediating apoptosis and inhibiting differentiation of osteoblast lineage cells. Modulation of Fas effects on bone cells may be used as a therapeutic target in the treatment of osteoresorptive disorders.


Neuroimmunomodulation | 2014

Decreased level of sRAGE in the cerebrospinal fluid of multiple sclerosis patients at clinical onset.

Anton Glasnović; Hrvoje Cvija; Maristela Stojić; Ivana Tudorić-Đeno; Sanja Ivčević; Dominik Romić; Nino Tičinović; Vladimira Vuletić; Ines Lazibat; Danka Grčević

Objectives: Receptor for advanced glycation end products (RAGE) ligands/RAGE interactions have been proposed to have a pathogenic role in neuroinflammatory disorders. Our study aimed to assess changes in high-mobility group box (HMGB)1 and its receptor RAGE in peripheral blood (PBL) and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) at the disease onset compared with control subjects. Methods: PBL and CSF were collected from control subjects (n = 30) and MS patients (n = 27) at clinical onset. Soluble RAGE (sRAGE), HMGB1, S100 calcium-binding protein A12 (S100A12), interleukin (IL)-1β and tumor necrosis factor (TNF)-α were measured in the CSF and plasma by enzyme-linked immunosorbent assay. Gene expression in PBL mononuclear cells (PBMCs) was detected by quantitative PCR for RAGE, HMGB1, S100A12 and several proinflammatory/immunoregulatory cytokines. Results: We found a significantly lower expression of IL-10 (p = 0.031) in the PBMCs of MS patients. The level of sRAGE in the CSF of MS patients was lower (p = 0.021), with the ability to discriminate between MS patients and control subjects. Moreover, PBMC gene expression for HMGB1 and S100A12 positively correlated with IL-6. Conclusions: Our study confirmed that the cytokine network is disturbed in PBL and CSF at MS clinical onset. The deregulated HMGB1/RAGE axis found in our study may present an early pathogenic event in MS, proposing sRAGE as a possible novel therapeutic strategy for MS treatment.


Inflammation | 2012

Chemotactic and Immunoregulatory Properties of Bone Cells are Modulated by Endotoxin-Stimulated Lymphocytes

Hrvoje Cvija; Nataša Kovačić; Vedran Katavić; Sanja Ivčević; Hector L. Aguila; Ana Marušić; Danka Grčević

In our study, we explored the bidirectional communication via soluble factors between bone cells and endotoxin-stimulated splenic lymphocytes in an in vitro coculture model that mimics the inflammatory environment. Both the ability of lymphocytes to affect differentiation and immune properties of bone cells, osteoblasts (OBL) and osteoclasts (OCL), and of bone cells to modulate cytokine and activation profile of endotoxin-stimulated lymphocytes were tested. LPS-pulsed lymphocytes enhanced OCL but inhibited OBL differentiation and increased the RANKL/OPG ratio, and, at the same time, upregulated chemotactic properties of bone cells, specifically CCL2, CCL5, and CXCL10 in OCL and CCL5 and CXCL13 in OBL. In parallel, bone cells had immunosuppressive effects by downregulating the lymphocyte expression of interleukin (IL)-1, IL-6, TNF-α and co-stimulatory molecules. OCL stimulated the production of osteoclastogenic cytokine RANKL in T lymphocytes. The anti-inflammatory effect, especially of OBL, suggests a possible compensatory mechanism to limit the inflammatory reaction during infection.


Clinical and Experimental Immunology | 2016

Increased chemotaxis and activity of circulatory myeloid progenitor cells may contribute to enhanced osteoclastogenesis and bone loss in the C57BL/6 mouse model of collagen-induced arthritis.

M. Ikić Matijašević; Darja Flegar; Nataša Kovačić; Vedran Katavić; Tomislav Kelava; Alan Šućur; Sanja Ivčević; Hrvoje Cvija; E. Lazić Mosler; Ivo Kalajzic; Ana Marušić; Danka Grčević

Our study aimed to determine the functional activity of different osteoclast progenitor (OCP) subpopulations and signals important for their migration to bone lesions, causing local and systemic bone resorption during the course of collagen‐induced arthritis in C57BL/6 mice. Arthritis was induced with chicken type II collagen (CII), and assessed by clinical scoring and detection of anti‐CII antibodies. We observed decreased trabecular bone volume of axial and appendicular skeleton by histomorphometry and micro‐computed tomography as well as decreased bone formation and increased bone resorption rate in arthritic mice in vivo. In the affected joints, bone loss was accompanied with severe osteitis and bone marrow hypercellularity, coinciding with the areas of active osteoclasts and bone erosions. Flow cytometry analysis showed increased frequency of putative OCP cells (CD3–B220–NK1.1–CD11b–/loCD117+CD115+ for bone marrow and CD3–B220–NK1.1–CD11b+CD115+Gr‐1+ for peripheral haematopoietic tissues), which exhibited enhanced differentiation potential in vitro. Moreover, the total CD11b+ population was expanded in arthritic mice as well as CD11b+F4/80+ macrophage, CD11b+NK1.1+ natural killer cell and CD11b+CD11c+ myeloid dendritic cell populations in both bone marrow and peripheral blood. In addition, arthritic mice had increased expression of tumour necrosis factor‐α, interleukin‐6, CC chemokine ligand‐2 (Ccl2) and Ccl5, with increased migration and differentiation of circulatory OCPs in response to CCL2 and, particularly, CCL5 signals. Our study characterized the frequency and functional properties of OCPs under inflammatory conditions associated with arthritis, which may help to clarify crucial molecular signals provided by immune cells to mediate systemically enhanced osteoresorption.


Frontiers in Immunology | 2018

The Long Pentraxin 3 Plays a Role in Bone Turnover and Repair

Danka Grčević; Marina Sironi; Sonia Valentino; Livija Deban; Hrvoje Cvija; Antonio Inforzato; Nataša Kovačić; Vedran Katavić; Tomislav Kelava; Ivo Kalajzic; Alberto Mantovani; Barbara Bottazzi

Pentraxin 3 (PTX3) is an inflammatory mediator acting as a fluid-phase pattern recognition molecule and playing an essential role in innate immunity and matrix remodeling. Inflammatory mediators also contribute to skeletal homeostasis, operating at multiple levels in physiological and pathological conditions. This study was designed to investigate the role of PTX3 in physiological skeletal remodeling and bone healing. Micro-computed tomography (μCT) and bone histomorphometry of distal femur showed that PTX3 gene-targeted female and male mice (ptx3−/−) had lower trabecular bone volume than their wild-type (ptx3+/+) littermates (BV/TV by μCT: 3.50 ± 1.31 vs 6.09 ± 1.17 for females, p < 0.0001; BV/TV 9.06 ± 1.89 vs 10.47 ± 1.97 for males, p = 0.0435). In addition, μCT revealed lower trabecular bone volume in second lumbar vertebra of ptx3−/− mice. PTX3 was increasingly expressed during osteoblast maturation in vitro and was able to reverse the negative effect of fibroblast growth factor 2 (FGF2) on osteoblast differentiation. This effect was specific for the N-terminal domain of PTX3 that contains the FGF2-binding site. By using the closed transversal tibial fracture model, we found that ptx3−/− female mice formed significantly less mineralized callus during the anabolic phase following fracture injury compared to ptx3+/+ mice (BV/TV 17.05 ± 4.59 vs 20.47 ± 3.32, p = 0.0195). Non-hematopoietic periosteal cells highly upregulated PTX3 expression during the initial phase of fracture healing, particularly CD51+ and αSma+ osteoprogenitor subsets, and callus tissue exhibited concomitant expression of PTX3 and FGF2 around the fracture site. Thus, PTX3 supports maintenance of the bone mass possibly by inhibiting FGF2 and its negative impact on bone formation. Moreover, PTX3 enables timely occurring sequence of callus mineralization after bone fracture injury. These results indicate that PTX3 plays an important role in bone homeostasis and in proper matrix mineralization during fracture repair, a reflection of the function of this molecule in tissue homeostasis and repair.


European Calcified Tissue Society Congress 2014 | 2014

Increased expression of PTX3 in non-hematopoietic periosteal cells during fracture healing

Tomislav Kelava; Sanja Ivčević; Vedran Katavić; Nataša Kovačić; Hrvoje Cvija; Katerina Zrinski Petrović; Sania Kuzmac; Ivo Kalajzic; Barbara Bottazzi; Danka Grčević


PLOS ONE | 2013

Critical role for PTX3 in bone regeneration and fracture healing

Tomislav Kelava; Sanja Ivčević; Vedran Katavić; Nataša Kovačić; Hrvoje Cvija; Sania Kuzmac; Ivo Kalajzic; Barbara Bottazzi; Danka Grčević


2nd Meeting of Middle-European Societies for Immunology and Allergology: Book of Abstracts | 2013

The important role of Pentraxin 3 in bone formation and fracture healing

Tomislav Kelava; Sanja Ivčević; Vedran Katavić; Nataša Kovačić; Hrvoje Cvija; Sania Kuzmac; Ivo Kalajzic; Barbara Bottazzi; Danka Grčević


THE ANNUAL SYMPOSIUM OF THE CROATIAN PHYSIOLOGICAL SOCIETY WITH INTERNATIONAL PARTICIPATION. | 2012

Effect of lipopolysaccharide on osteoclast and osteoblast differentiation in vitro

Alan Šućur; Danka Grčević; Elvira Lazic Mosler; Sanja Ivčević; Hrvoje Cvija; Nataša Kovačić; Ana Marušić

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Ivo Kalajzic

University of Connecticut Health Center

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Barbara Bottazzi

Mario Negri Institute for Pharmacological Research

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