osteoprotegerin and Histiocytosis--Langerhans-Cell

An etiological treatment is currently lacking for Langerhans Cell Histiocytosis (LCH). Receptor activator of nuclear factor κB ligand (RANKL) appears to play a central role in the lesional immunological process inducing compensatory osteoprotegerin (OPG) activation. In a preliminary study we aimed to evaluate for the first time the use of denosumab, a RANKL inhibitor, as a targeted treatment strategy in LCH in order to support and enhance endogenous OPG action in order to control or alter the lesional immunological process.. Two adult female patients with painful osteolytic bone lesions and concomitant pulmonary involvement received bimonthly denosumab 120mg in a total of 4 doses.. Both patients reported an immediate pain relief within the first two weeks following the 1st dose of denosumab. One month following the last dose an almost full remission of the initial osteolytic and lung lesions was observed, although an apparent new bone lesion was detected in one patient that was treated with a single intralesional steroid injection. No adverse events were recorded throughout the treatment period. Both patients have no active disease 6months following the last denosumab dose.. Denosumab could be considered an effective treatment option in adults with multisystem LCH also exerting a significant analgesic effect in bone lesions, warranting further investigation.

Topics: Adult; Bone Density Conservation Agents; Bone Diseases; Denosumab; Female; Histiocytosis, Langerhans-Cell; Humans; Lung Diseases; Magnetic Resonance Imaging; Osteoprotegerin; Pain; Positron-Emission Tomography; RANK Ligand; Treatment Outcome

Langerhans cell histiocytosis (LCH) is a rare disease caused by the clonal accumulation of dendritic Langerhans cells, which is often accompanied by osteolytic lesions. It has been reported that osteoclast-like cells play a major role in the pathogenic bone destruction seen in patients with LCH and these cells are postulated to originate from the fusion of DCs. However, due to the lack of reliable animal models the pathogenesis of LCH is still poorly understood. In this study, we have established a mouse model of histiocytosis- recapitulating human disease for osteolytic lesions seen in LCH patients. At 12 weeks after birth, severe bone lesions were observed in our multisystem histiocytosis (Mushi) model, when CD8α conventional dendritic cells (DCs) are transformed (MuTuDC) and accumulate. Most importantly, our study demonstrates that bone loss in LCH can be accounted for the transdifferentiation of MuTuDCs into functional osteoclasts both in vivo and in vitro. Moreover, we have shown that injected MuTuDCs reverse the osteopetrotic phenotype of oc/oc mice in vivo. In conclusion, our results support a crucial role of DCs in bone lesions in histiocytosis patients. Furthermore, our new model of LCH based on adoptive transfer of MuTuDC lines, leading to bone lesions within 1-2 weeks, will be an important tool for investigating the pathophysiology of this disease and ultimately for evaluating the potential of anti-resorptive drugs for the treatment of bone lesions.

Topics: Animals; Bone and Bones; Bone Density Conservation Agents; Cell Line; Cell Transdifferentiation; Dendritic Cells; Diphosphonates; Disease Models, Animal; Histiocytosis, Langerhans-Cell; Humans; Langerhans Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Osteoclasts; Osteolysis; Osteoprotegerin

Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology with a strong evidence of immunological dysfunction secondary to cytokine dysregulation.. This study aimed to evaluate serum receptor activator of nuclear factor κB ligand (RANKL), osteoprotegerin (OPG), and Dickkopf-1 (Dkk-1) levels in adult patients with LCH at various stages of the disease.. This was a cross-sectional study in an adult LCH cohort followed for 12.2 ± 2.1 yr.. The study was conducted in an outpatient clinic.. Twenty-five adult patients with a definitive LCH diagnosis and 50 matched controls participated in the study.. Early morning, fasting, venous sampling was conducted in all subjects.. We compared RANKL, OPG, and Dkk-1 serum levels between patients and controls, as well as their association with disease parameters.. Serum OPG levels were significantly higher (3.0 ± 0.2 vs. 1.7 ± 0.1 pmol/liter; P < 0.001), whereas RANKL/OPG ratio was significantly lower (0.201 ± 0.041 vs. 0.471 ± 0.072; P = 0.02) in LCH patients compared to controls. Both higher OPG (adjusted odds ratio, 3.431; 95% confidence interval, 1.329-8.924) and lower RANKL (adjusted odds ratio, 0.144; 95% confidence interval, 0.034-0.605) levels were independently associated with LCH in logistic regression analysis, after adjustment for all other parameters. Dkk-1 did not differ among patients and controls.. Adults with LCH have high serum OPG levels and low serum RANKL levels. In contrast with other disorders involving the skeleton, serum Dkk-1 levels are similar between LCH patients and controls.

Topics: Adult; Aged; Algorithms; Biomarkers; Cohort Studies; Cross-Sectional Studies; Female; Follow-Up Studies; Histiocytosis, Langerhans-Cell; Humans; Intercellular Signaling Peptides and Proteins; Logistic Models; Male; Middle Aged; Osteoprotegerin; Outpatient Clinics, Hospital; RANK Ligand; Recurrence; Remission, Spontaneous; Young Adult

To determine useful biochemical markers in Langerhans cell histiocytosis (LCH), we analyzed the serum levels of soluble CD154 (sCD154), IL2 receptor (sIL2-R), receptor activator of NF-kappaB ligand (sRANKL), and osteoprotegerin (OPG).. Our study included 46 newly diagnosed LCH patients (single-system multi-site (SM type): n = 20, and multi-system multi-site (MM type): n = 26) who were treated with the JLSG-02 protocol between 2002 and 2004. The median age of the patients was 3.8 years old (range 0-18). sCD154, sIL2-R, sRANKL, and OPG were measured by ELISA at diagnosis (n = 46) and after 6-weeks of induction therapy (n = 14).. The values of sCD154, sIL-2R, sRANKL, and OPG, and the sRANKL/OPG ratio in sera were significantly higher in patients with LCH compared with controls (1.83 +/- 1.38 vs. 0.22 +/- 0.16 ng/ml, P < 0.001; 1,600 +/- 1,060 vs. 420 +/- 160 pg/ml, P < 0.001; 1.72 +/- 1.20 vs. 1.04 +/- 1.09 pmol/L, P = 0.019; 6.34 +/- 2.94 vs. 3.71 +/- 2.03 pmol/L, P < 0.001; and 0.40 +/- 0.45 vs. 0.16 +/- 0.17, P = 0.023, respectively). Serum levels of sIL-2R were significantly elevated in the MM type compared with the SM type (2,050 +/- 1,060 vs. 870 +/- 340 pg/ml, P < 0.001). Serum OPG levels were also significantly elevated in the MM type compared with the SM type (7.58 +/- 2.72 vs. 5.13 +/- 2.69 pmol/L, P = 0.008) and negatively correlated with the number of bone lesions (r = -0.56, P = 0.007). In contrast, the sRANKL/OPG ratios were significantly higher in the SM type than the MM type (0.57 +/- 0.54 vs. 0.19 +/- 0.14, P = 0.002) and positively correlated with the number of bone lesions (r = 0.34, P = 0.040). In patients who responded to the induction therapy, serum levels of sIL-2R, sRANKL, and OPG, and the sRANKL/OPG ratio decreased significantly after the therapy (1,170 +/- 600 vs. 730 +/- 290 pg/ml, P = 0.029; 2.19 +/- 1.06 vs. 1.24 +/- 0.66 pmol/L, P < 0.001; 6.13 +/- 2.40 vs. 4.72 +/- 2.03 pmol/L, P = 0.040; and 0.57 +/- 0.52 vs. 0.41 +/- 0.37, P = 0.02, respectively). In the three patients who did not respond to the induction therapy, the serum levels of sCD154 increased significantly after the therapy (1.3 +/- 1.1 vs. 2.7 +/- 1.2, P = 0.004).. Serum levels of sIL-2R and sCD154 could be useful as indicators of inflammation and sRANKL/OPG ratios as markers of osteolytic activity in LCH patients.

Topics: Adolescent; Biomarkers; Carrier Proteins; Case-Control Studies; CD40 Ligand; Child; Child, Preschool; Female; Glycoproteins; Histiocytosis, Langerhans-Cell; Humans; Infant; Infant, Newborn; Male; Membrane Glycoproteins; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Interleukin-2; Receptors, Tumor Necrosis Factor

Langerhans cell histiocytosis (LCH) is characterized by an accumulation of dendritic Langerhans cells in granulomatous lesions in the bone, skin, and other sites in the body. The pathogenesis of the disease remains unknown. We measured serum levels of the decoy receptor osteoprotegerin (OPG), an important regulator of bone metabolism as well as immune responses, in 18 children with single system (SS) or multi-system (MS) forms of LCH and 20 pediatric controls. OPG levels were significantly increased in LCH patients at diagnosis when compared with controls, and pretreatment levels of OPG were elevated in MS compared with SS patients. Moreover, OPG levels in LCH patients were elevated in patients with involvement of risk organs (liver, lungs, hematopoietic system, or spleen) when compared with patients without risk organ involvement, indicative of an association between OPG values and disease severity. We also observed a positive correlation between serum levels of OPG and tumor necrosis factor (TNF)-alpha, a pro-inflammatory cytokine, at the time of onset of disease. These findings show, for the first time, that serum OPG levels are elevated in LCH patients, and suggest that OPG may play a role in the pathogenesis of this enigmatic disease.

Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Female; Glycoproteins; Histiocytosis, Langerhans-Cell; Humans; Infant; Male; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor