osteoprotegerin and Jaw-Diseases

Central giant cell granuloma (CGCG) is a benign lesion of the jaws with an unknown etiology. Clinically and radiologically, a differentiation between aggressive and non-aggressive lesions can be made. The incidence in the general population is very low and patients are generally younger than 30 years. Histologically identical lesions occur in patients with known genetic defects such as cherubism, Noonan syndrome, or neurofibromatosis type 1. Surgical curettage or, in aggressive lesions, resection, is the most common therapy. However, when using surgical curettage, undesirable damage to the jaw or teeth and tooth germs is often unavoidable and recurrences are frequent. Therefore, alternative therapies such as injection of corticosteroids in the lesion or subcutaneous administration of calcitonin or interferon alpha are described in several case reports with variable success. Unfortunately, randomized clinical trials are very rare or nonexistent. In the future, new and theoretically promising therapy options, such as imatinib and OPG/AMG 162, will be available for these patients.

Topics: Adrenal Cortex Hormones; Age Distribution; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Bone Density Conservation Agents; Calcitonin; Denosumab; Giant Cell Tumor of Bone; Granuloma, Giant Cell; Humans; Imatinib Mesylate; Interferons; Jaw Diseases; Osteoprotegerin; Piperazines; Pyrimidines; RANK Ligand; Subgingival Curettage

The aim of this study was to evaluate the immunohistochemical expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and of osteoprotegerin (OPG), important proteins correlated with osteoclastogenesis, in central giant cell lesions (CGCL) and peripheral giant cell lesions (PGCL) and to compare their expression with the histological and clinical parameters for quantification of multinucleated giant cells (MGC) and their nuclei, lesion size, and recurrences. Twenty cases of each lesion type were selected to quantify the number of MGCs and nuclei/mm2 of connective tissue. The immunoreactivity of RANKL and OPG was expressed as a percentage of the marked area in the stroma. Clinical data were collected from pathoanatomical and medical reports. No statistical differences were found for the number of MGCs (p = 0.24) between PGCL and CGCL, but the number of nuclei within the MGCs was higher in CGCL (p = 0.01). RANKL expression was higher in CGCL than in PGCL (p = 0.04) and all recurrent lesions showed higher RANKL and OPG expressions than nonrecurrent lesions. We report higher RANKL expression and a greater number of nuclei in CGCL, which may explain the difference in clinical behaviour between these lesions and their pathogenesis.

Topics: Adolescent; Adult; Child; Female; Giant Cells; Granuloma, Giant Cell; Humans; Immunohistochemistry; Jaw Diseases; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; RANK Ligand; Reference Values; Retrospective Studies; Statistics, Nonparametric; Young Adult

Bisphosphonate induced osteonecrosis of the jaw (BONJ) is a complication in patients taking bisphosphonate (BP) that affects their quality of life and compliance. In this cohort study, patients with multiple myeloma (MM) on intravenous BP therapy were enrolled over 1 year. Demographic and clinical data and genotyping of 10 single nucleotide polymorphisms (SNPs) from seven candidate genes associated with drug or bone metabolism were determined. Of the 78 patients enrolled, 12 had BONJ. The median time to developing BONJ was 28 months. Univariate and multivariate analysis revealed a significant association between BONJ and smoking (p=0.048) and type of BP treatment (p=0.03). A trend for higher odds for BONJ was found for SNPs in five genes: COL1A1 (rs1800012), RANK (rs12458117), MMP2 (rs243865), OPG (rs2073618) and OPN (rs11730582). Considering all five SNPs together, patients with genotype scores ≥ 5 had a BONJ event rate of 57%; those with scores < 5 had a rate of 10%. The adjusted odds ratio was 11.2 (95% confidence interval of 1.8-69.9; p value 0.0097). Smoking, type of BP and combined genotype score of COL1A1, RANK, MMP2, OPG and OPN were significantly associated with BONJ in MM patients undergoing BP therapy.

Topics: Adult; Aged; Aryl Hydrocarbon Hydroxylases; Bone Density Conservation Agents; Cohort Studies; Collagen Type I; Collagen Type I, alpha 1 Chain; Cytochrome P-450 CYP2C8; Diphosphonates; Female; Gene Frequency; Humans; Imidazoles; Injections, Intravenous; Jaw Diseases; Male; Matrix Metalloproteinase 2; Middle Aged; Multiple Myeloma; Osteonecrosis; Osteopontin; Osteoprotegerin; Pamidronate; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptor Activator of Nuclear Factor-kappa B; Risk Factors; Smoking; Time Factors; Tumor Necrosis Factor-alpha; Zoledronic Acid

Peripheral giant cell granuloma is a tumor of the jaw characterized by the presence of multinucleated giant cells and mononuclear cells within a fibrous stroma. These lesions are considered to be of a reactive nature rather than neoplastic. Although peripheral giant cell granulomas is a well-described clinical entity, little is known on its pathogenesis. The aim of this study was to investigate the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) expression and immunolocalization in giant cell granulomas.. RANKL and OPG protein expression was evaluated in 22 peripheral giant cell granulomas samples, by means of immunohistochemistry. Staining was evaluated semi-quantitatively, according to the extent and intensity of the stain.. RANKL was expressed in all cases with a cytoplasmic staining pattern, whereas OPG expression was detected in 21 of the 22 cases examined. Active multinucleated giant cells exhibited intense immunoreactivity for both proteins.. RANKL and OPG are expressed in peripheral giant cell granulomas of the jaw in a manner supporting the osteoclastic nature of giant cells whereas the possible osteoclastic lineage of stromal monocytes remains ambiguous.

Topics: Cell Lineage; Fibroblasts; Granuloma, Giant Cell; Humans; Immunohistochemistry; Jaw Diseases; Osteoclasts; Osteoprotegerin; RANK Ligand; Stromal Cells

The aim of this study was to investigate the expression of bone resorption (RANK/RANKL), bone resorption inhibitor (osteoprotererin [OPG]), and bone formation marker (osteocalcin [OC]) in neoplastic and bone-related lesions (BRL).. Using immunohistochemistry, their expression was evaluated in ossifying fibroma (OF), fibrous dysplasia (FD), simple bone cysts (SBC), central giant cell lesions (CGCL), and osteosarcoma (OS).. Quantitative analyses of the expression of bone markers between all lesions, considering fibroblast-like cells and bone matrix, showed that RANK-RANKL presented higher expression in OF and CGCL, whereas OPG and OC presented higher expression in FD and SBC. There was higher expression of all proteins investigated when OS was the BRL. Moreover, the RANKL expression was greater than OPG in this neoplasm.. Our data indicate that the bone resorption markers are more highly expressed in OF, CGCL, and OS than in FD and SBC, indicating a significant association between these proteins and the clinical behavior of these lesions.

Topics: Adolescent; Adult; Biomarkers; Biomarkers, Tumor; Bone Matrix; Bone Remodeling; Bone Resorption; Child; Female; Fibroblasts; Fibroma, Ossifying; Fibrous Dysplasia of Bone; Giant Cells; Granuloma, Giant Cell; Humans; Jaw Cysts; Jaw Diseases; Jaw Neoplasms; Male; Middle Aged; Osteoblasts; Osteocalcin; Osteoclasts; Osteogenesis; Osteoprotegerin; Osteosarcoma; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Stromal Cells; Young Adult

To detect the expression of RANKL and OPG protein in the giant cell lesions of jaw and to study the mechanism of this lesion.. RANKL and OPG were detected by immunohistochemistry (SP) in 24 paraffin-embedded and 2 frozen specimens of central giant cell lesion of jaw.. RANKL signals were strongly positive in the vascular epithelial cells. They also could be found in fibrous stroma, bone matrix, and stromal spindle cells, even in some cytomembrane of multinucleated giant cells. OPG was detected in multinucleated giant cells and a fraction of round mononuclear cells.. Active vascular epithelial cells are contributed to the formation of multinucleated giant cells through regulating RANKL, and RANKL could play its role by paracrine and autocrine, which might be inhibited by OPG.

Topics: Giant Cells; Humans; Jaw Diseases; Osteoclasts; Osteoprotegerin; RANK Ligand

The nature and the mechanism involved in the formation of the multinucleated giant cells (MGCs) in various giant cell-containing lesions of the jaws are not fully understood. The aim of this study is to clarify the osteoclastic features of the MGCs in central giant cell granuloma (CGCG), peripheral giant cell granuloma (PGCG), cherubism, and aneurysmal bone cyst (ABC), and the mechanism underlying the interrelations between cellular components in the formation of the MGCs.. Immunohistochemical study with a panel of antibodies including vacuolar H+-ATPase (V-ATPase), carbonic anhydrase II (CA II), Cathepsin K, matrix metalloproteinases-9 (MMP-9), CD68, and proliferating cell nuclear antigen (PCNA), and enzyme histochemical staining for tartarate-resistant acid phosphatase (TRAP) were applied on a total number of 53 cases of giant cell-containing lesions including CGCG (n = 34), PGCG (n = 6), cherubism (n = 7), and ABC (n = 6). In situ hybridization was also carried out to detect the mRNA expression of the receptor activator of NF-kappaB ligand (RANKL), a newly identified cytokine that is shown to be essential in the osteoclastogenesis, its receptor RANK (receptor activator of NF-kappaB ligand), and its decoy receptor OPG (osteoprotegerin) in these four types of lesions.. Immunohistochemical and enzyme histochemical studies showed that both the MGCs and a fraction of mononuclear cells in these lesions were strongly positive for TRAP, V-ATPase, CA II, Cathepsin K, MMP-9, and CD68, while the spindle-shaped mononuclear cells were positive for PCNA. The results with in situ hybridization indicated that RANKL mRNA was mainly expressed in the spindle mononuclear cells while OPG was extensively distributed in both the MGCs and the mononuclear cells. RANK mRNA was expressed in the MGCs and some round mononuclear cells.. These results suggest that MGCs in the four types of giant cell-containing lesions of the jaws show characteristics of the osteoclast phenotype. The mononuclear stromal cells, which show TRAP positively, may be the precursors of the MGCs. RANKL, OPG, and RANK expressed in these lesions may play important roles in the formation of the MGCs. The similar characteristics and mechanisms in the differentiation of MGCs in these lesions also suggest that there might be a similar kind of pathogenesis involved in the formation of the MGCs in these lesions

Topics: Bone Cysts, Aneurysmal; Carrier Proteins; Cell Differentiation; Cherubism; Gene Expression Regulation, Developmental; Giant Cells; Glycoproteins; Granuloma, Giant Cell; Humans; Immunohistochemistry; In Situ Hybridization; Jaw Diseases; Membrane Glycoproteins; Osteoclasts; Osteoprotegerin; Phenotype; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; RNA, Messenger