scholarly journals Comment on "The B Cell-Stimulatory Cytokines BLyS and APRIL Are Elevated in Human Periodontitis and Are Required for B Cell-Dependent Bone Loss in Experimental Murine Periodontitis."

2015 ◽  
Vol 195 (11) ◽  
pp. 5099-5099 ◽  
Author(s):  
M. Zhu ◽  
B. S. Nikolajczyk
Keyword(s):  
Bone Loss ◽  
B Cell

scholarly journals B Cell Specific Knockdown of the Erythropoietin (EPO) Receptor Attenuates EPO-Induced Bone Loss in Mice

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 939-939
Author(s):  
Albert Kolomansky ◽  
Naamit Deshet-Unger ◽  
Nathalie Ben-Califa ◽  
Zamzam Awida ◽  
Maria Ibrahim ◽  
...  
Keyword(s):  
B Cells ◽  
Bone Loss ◽  
B Cell ◽  
Trabecular Bone ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Trabecular Bone Loss ◽  
Β3 Integrin ◽  
First Time

Background and aims: Erythropoietin (EPO) is the key regulator of red blood cell production, commonly used in clinical practice to treat certain forms of anemia. Our studies and those of others have demonstrated that EPO administration induces substantial trabecular bone loss. We proposed that EPO-induced bone loss is partially mediated by subsets of bone marrow (BM) B cells that express EPO-R. Mechanistically, EPO upregulates the surface expression of RANKL by BM B cells and augments B cell-derived osteoclastogenesis in vitro. We showed that the latter is likely mediated by pro-B cells expressing the MCS-F receptor (CD115) and capable of transdifferentiation to osteoclasts (Abstract # 1007, EHA 2017). Here we address the role of B cell-specific EPO-R in EPO-induced bone loss (i.e. at supra-physiological EPO levels). Moreover, we demonstrate, for the first time, the occurrence of B cell-derived osteoclastogenesis in vivo, a finding of critical importance in the field of osteohematology. Methods: In order to trace the B cell lineage from its earliest precursors, we used the MB1-Cre mouse line combined with either the R26R-EYFP or the EPO-Rfl/fl mice for lineage tracing and B cell-specific EPO-R knockdown, respectively. Sequential fluorescence and light microscopy were used for the demonstration of B cell-derived osteoclastogenesis in vivo. Human recombinant EPO was administered in vivo at a dose of 180IU thrice weekly for two weeks. Immunophenotyping of BM B cell populations was assessed by multi-color flow cytometry. Results: Using female MB1-Cre; EPO-Rfl/fl (cKD) mice, we found that B cell-specific EPO-R knockdown attenuated the profound EPO-induced trabecular bone loss in the proximal part of the femoral distal metaphysis (proximal BV/TV 0.034±0.012% vs 0.007±0.003% in the cKD vs control mice, p<0.05, Figure 1). Remarkably, this effect was observed despite the fact that cKD mice attained higher hemoglobin levels following EPO treatment (21.1±0.1 mg/dL vs 20.4±0.2 mg/dL in the cKD vs control mice, p<0.05). An EPO-induced increase in CD115+ Pro-B cells was observed in EPO-treated control mice but was absent in the cKD mice. The latter finding correlates with the observed bone loss and indicates that the increased number of MCSF-R-expressing pro-B cells is dependent on B cell EPO-R. Supporting the osteoclastic potential of this specific B cell subpopulation is the fact that most of the CD115+ Pro-B cells also express β3 integrin (CD61) which is essential for osteoclast differentiation and function. Using the MB1-Cre;R26R-EYFP murine model for B cell lineage tracing, we could demonstrate that some of the TRAP+/ β3 integrin+ bone lining cells were also positive for EYFP (Figure 2). This demonstrates the B cell origin of some of the osteoclasts in vivo. Conclusions: Our work highlights B cells as an important extra-erythropoietic target of EPO-EPO-R signaling that regulates bone homeostasis and might also indirectly affect EPO-stimulated erythropoietic response. The relevance and the mechanisms of the latter phenomenon merits further investigation. Importantly, we present here, for the first time, histological evidence for B cell-derived osteoclastogenesis in vivo, thus opening novel research avenues. DN and YG Equal contribution Funded by the German Israel Foundation, Grant # 01021017 to YG, DN, MR and BW and by the Israel Science Foundation (ISF) Grant No. 343/17 to DN. Disclosures Mittelman: Novartis: Honoraria, Research Funding, Speakers Bureau.

RANK-RANKL Mediated Bone Destruction in B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 908-908 ◽  
Author(s):  
Sujeetha A. Rajakumar ◽  
Eniko Papp ◽  
Ildiko Grandal ◽  
Daniele Merico ◽  
Careesa C. Liu ◽  
...  
Keyword(s):  
Bone Loss ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Bone Destruction ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Survival rates for pediatric B-Cell Acute Lymphoblastic Leukemia (B-ALL) have improved dramatically over the past 40 years approaching a current long-term survival rate of 85%. However childhood B-ALL patients continue to confront co-morbidities and their long-term consequences. For example, osteopenia and osteoporosis associated fractures are a common complication of pediatric leukemia at diagnosis, during treatment and in long-term B-ALL survivors. The STeroid-associated Osteoporosis in the Pediatric Population (STOPP) study reported that at ALL diagnosis, 16% of children and adolescents present with bone pain, vertebral compression and low vertebral Bone Mineral Density (BMD) scores, with the greatest incidence of vertebral fractures (VF) seen in the first year following diagnosis (J Clin Endocrinol Metab. 2015, 100:3408-17). Glucocorticoid treatment further elevated fracture risk in this population. These data underscore the need to identify molecular mechanism by which leukemic cells contribute to bone loss, and provide targeted therapies to limit these effects. Our laboratory previously showed that Rag2-/- p53-/- Prkdcscid/scid triple mutant (TM) and p53-/- Prkdcscid/scid double mutant (DM) mice develop spontaneous B-ALL, but only TM animals exhibit dissemination of leukemic blasts to the leptomeninges of the CNS, a poor prognosis feature observed in pediatric and adult ALL patients. We observed that TM leukemic mice also displayed fragile vertebral bones. Using comparative transcriptome analysis, we found that RANKL (Receptor Activator of the Nuclear factor-kB Ligand), a Tumor Necrosis Factor (TNF) superfamily member ligand and a key regulator of B cell and osteoclast differentiation, was expressed at greater levels in TM compared to the DM leukemia cells. RANKL binds to its receptor RANK, which is expressed in osteoclast precursor cells. RANK-RANKL interaction induces signaling in the osteoclast precursors and drives their differentiation into mature bone resorbing osteoclasts (Proc. Natl. Acad. Sci. 1999, 96:3540-3545). Upon adoptive leukemia cell transfer into immune deficient mice, RANKL+ TM but not DM cells caused decreased vertebral trabecular bone density in the recipients. Treatment with the recombinant RANKL antagonist protein Osteoprotegerin (OPG-Fc) inhibited the growth and dissemination of RANKL+TM leukemic cells and attenuated bone destruction in the recipient mice. These data suggested that TM mouse leukemia cells cause bone loss in the absence of glucocorticoid or other chemotherapy agents. We then examined the potential role of RANKL in osteoporosis associated with human B-ALL. RANKL mRNA was expressed by a majority of primary human adult and pediatric B-ALL. To determine whether primary patient B-ALL can cause bone loss, we transplanted RANKL+ human B-ALL samples of multiple cytogenetic high-risk subgroups (Complex, hypo-diploid and Mixed Lineage Leukemia (MLL) rearranged) into NOD.SCID.gC-/-(NSG) recipient mice. Micro-CT imaging and bone density measures in the xenotransplant recipients revealed extensive vertebral trabecular bone destruction. Immuno-histological analysis of the human B-ALL recipient mice demonstrated extensive osteoporotic damage of the long bones and marked RANKL protein expression in the long bones of mice harboring extensive human B-ALL cell burden compared to NSG control mice. To determine whether RANKL-RANK interaction was required for the B-ALL mediated bone destruction, cohorts of NSG mice engrafted with human B-ALL were treated with recombinant OPG-Fc compared to a matched Fc control protein. OPG-Fc treatment did not attenuate leukemia cell expansion and bone marrow burden, but despite bulky disease, the treatment conferred robust protection from bone destruction suggesting that RANKL was a critical mediator of this clinical complication. Our data demonstrate a central role of the RANK-RANKL axis in B-ALL-mediated bone disease and identify an actionable therapeutic target to reduce acute and long-term morbidity. Denosumab, an anti-RANKL antibody has been approved for the treatment of bone metastasis by solid tumors and for post-menopausal osteoporosis. Our pre-clinical studies suggest that Denosumab and other agents that inhibit the RANK-RANKL pathway may be efficacious in patients with B-ALL associated bone degeneration. Disclosures No relevant conflicts of interest to declare.

scholarly journals B10 Cells Alleviate Periodontal Bone Loss in Experimental Periodontitis

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Yuhua Wang ◽  
Xiaoqian Yu ◽  
Jiang Lin ◽  
Yang Hu ◽  
Qian Zhao ◽  
...  
Keyword(s):  
B Cells ◽  
Bone Loss ◽  
B Cell ◽  
Cell Transfer ◽  
Content Type ◽  
Periodontal Inflammation ◽  
Periodontal Bone Loss ◽  
Experimental Periodontitis ◽  
Transfer Group ◽  
B10 Cells

ABSTRACT B10 cells can regulate inflammatory responses in innate immunity. Toll-like receptors (TLRs) play an important role in B cell-mediated immune responses in periodontal disease. This study aimed to determine the effects of TLR-activated B10 cells on periodontal bone loss in experimental periodontitis. Spleen B cells isolated from C57BL/6J mice were cultured with Porphyromonas gingivalis lipopolysaccharide (LPS) and cytosine-phospho-guanine (CpG) oligodeoxynucleotides for 48 h. B10-enriched CD1dhi CD5+ B cells were sorted by flow cytometry and were adoptively transferred to recipient mice through tail vein injection. At the same time, P. gingivalis-soaked ligatures were placed subgingivally around the maxillary second molars and remained there for 2 weeks before the mice were euthanized. Interleukin-10 (IL-10) production and the percentage of CD1dhi CD5+ B cells were significantly increased with treatment with P. gingivalis LPS plus CpG compared to those in mice treated with P. gingivalis LPS or CpG alone. Mice with CD1dhi CD5+ B cell transfer demonstrated reduced periodontal bone loss compared to the no-transfer group and the group with CD1dlo CD5− B cell transfer. Gingival IL-10 mRNA expression was significantly increased, whereas expressions of receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG), tumor necrosis factor alpha (TNF-α), and IL-1β were significantly inhibited in the CD1dhi CD5+ B cell transfer group. The percentages of CD19+ IL-10+ cells, CD19+ CD1dhi CD5+ cells, and P. gingivalis-binding CD19+ cells were significantly higher in recovered mononuclear cells from gingival tissues of the CD1dhi CD5+ B cell transfer group than in tissues of the no-transfer group and the CD1dlo CD5− B cell transfer group. This study indicated that the adoptive transfer of B10 cells alleviated periodontal inflammation and bone loss in experimental periodontitis in mice.

Osteopenia and osteoporosis in untreated non-Hodgkin's lymphoma patients: An important and potentially treatable survivorship issue in lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9055-9055 ◽  
Author(s):  
M. A. Thompson ◽  
A. Huen ◽  
B. B. Toth ◽  
R. Vassilopoulou-Sellin ◽  
A. O. Hoff ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Bone Loss ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Alkylating Agents ◽  
Hodgkin's Lymphoma ◽  
Mineral Density ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Mantle Cell

9055 Background: Alkylating agents and steroids can cause premature osteoporosis, increasing the risk of vertebral and hip fracture. The bisphosphonate pamidronate every 3 months can reduce bone loss and the risk of new vertebral fractures in lymphoma patients receiving chemotherapy.(Kim et al., 2004 Am J Med) We are conducting a randomized study of the more potent bisphosphonate zoledronic acid in untreated non-Hodgkin's lymphoma (NHL) patients to study chemotherapy induced bone loss. Methods: During the accrual period, we report the baseline bone mineral density (BMD) characteristics for screened untreated NHL patients. Exclusion criteria included bone fractures, BMD T-scores worse than -2.0, CrCl < 60 mL/min, dental problems, prior bisphosphonate or significant steroid use. Patients accrued to the study were randomized to receive either: 1) oral calcium and vitamin D (Ca+D) or 2) Ca+D and 4 mg zoledronic acid IV at baseline and at 6 months. Results: Patient characteristics: 59 males and 55 females with median age 63 (range: 18–87). Lymphoma types: B-cell n=111, T-cell 3; follicular (FL) 56, diffuse large B-cell (DLBCL) 33, mantle cell 8, and others, totaling 114 patients. Of untreated NHL individuals screened for baseline BMD to date 11/114 (10%) had osteoporosis and 62/114 (54%) had osteopenia or osteoporosis. The lowest BMD was a T-score of -4.4. Other bone, dental, and endocrine abnormalities excluded some patients from treatment randomization. Patients with T scores < -2.0 were considered for off-study treatment with bisphosphonates. Osteopenia and osteoporosis were common across lymphoma subtypes: FL 25/56 (45%), DLBCL 20/33 (61%), mantle cell 6/8 (75%), and marginal zone 5/6 (83%). The low rate of osteopenia/osteoporosis of 25% for Burkitt/Burkitt-like lymphoma may reflect fast lymphoma kinetics without associated increase in bone loss. Conclusions: Baseline testing of BMD revealed osteopenia or osteoporosis in the majority of untreated NHL patients. This widely available and non-invasive test should be considered in untreated NHL patients. Our ongoing clinical trial will address the potential role of zoledronic acid in preserving bone density for survivors of NHL. ClinicalTrials.gov Identifier: NCT00352846 [Table: see text]

Pharmacological B Cell Depletion by Anti-CD20 Antibody Induces Trabecular Bone Loss in Mice

2017 ◽  
Vol 17 ◽  
pp. S377-S378
Author(s):  
Albert Kolomansky ◽  
Naamit Deshet-Unger ◽  
Alina Ostrovsky ◽  
Nathalie Ben-Califa ◽  
Sahar Hiram-Bab ◽  
...  
Keyword(s):  
Bone Loss ◽  
B Cell ◽  
Trabecular Bone ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Trabecular Bone Loss ◽  
Cd20 Antibody ◽  
Anti Cd20

B cell acute lymphoblastic leukemia cells mediate RANK-RANKL–dependent bone destruction

2020 ◽  
Vol 12 (561) ◽  
pp. eaba5942 ◽  
Author(s):  
Sujeetha A. Rajakumar ◽  
Eniko Papp ◽  
Kathy K. Lee ◽  
Ildiko Grandal ◽  
Daniele Merico ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Bone Loss ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Bone Destruction ◽  
Leukemic Cells ◽  
Bone Pathology ◽  
Trabecular Bone Loss ◽  
Cell Acute Lymphoblastic Leukemia

Although most children survive B cell acute lymphoblastic leukemia (B-ALL), they frequently experience long-term, treatment-related health problems, including osteopenia and osteonecrosis. Because some children present with fractures at ALL diagnosis, we considered the possibility that leukemic B cells contribute directly to bone pathology. To identify potential mechanisms of B-ALL–driven bone destruction, we examined the p53−/−; Rag2−/−; Prkdcscid/scid triple mutant (TM) mice and p53−/−; Prkdcscid/scid double mutant (DM) mouse models of spontaneous B-ALL. In contrast to DM animals, leukemic TM mice displayed brittle bones, and the TM leukemic cells overexpressed Rankl, encoding receptor activator of nuclear factor κB ligand. RANKL is a key regulator of osteoclast differentiation and bone loss. Transfer of TM leukemic cells into immunodeficient recipient mice caused trabecular bone loss. To determine whether human B-ALL can exert similar effects, we evaluated primary human B-ALL blasts isolated at diagnosis for RANKL expression and their impact on bone pathology after their transplantation into NOD.Prkdcscid/scidIl2rgtm1Wjl/SzJ (NSG) recipient mice. Primary B-ALL cells conferred bone destruction evident in increased multinucleated osteoclasts, trabecular bone loss, destruction of the metaphyseal growth plate, and reduction in adipocyte mass in these patient-derived xenografts (PDXs). Treating PDX mice with the RANKL antagonist recombinant osteoprotegerin–Fc (rOPG-Fc) protected the bone from B-ALL–induced destruction even under conditions of heavy tumor burden. Our data demonstrate a critical role of the RANK-RANKL axis in causing B-ALL–mediated bone pathology and provide preclinical support for RANKL-targeted therapy trials to reduce acute and long-term bone destruction in these patients.

scholarly journals Erythropoietin (EPO) Regulates Bone Mass Via EPO Receptors on Myeloid and Lymphocytic Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 846-846
Author(s):  
Sahar Hiram-Bab ◽  
Albert Kolomansky ◽  
Naamit Deshet-Unger ◽  
Nathalie Ben-Califa ◽  
Tamar Liron ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Bone Resorption ◽  
Bone Loss ◽  
Bone Mass ◽  
B Cell ◽  
Trabecular Bone ◽  
Conflicts Of Interest ◽  
New Findings ◽  
Equal Contribution

Abstract Background and aims: Erythropoietin (EPO) is the key regulator of red blood cell production. In response to hypoxia, EPO levels can increase 1000-fold and remain high for weeks to promote hematopoiesis. Therapeutically, the introduction of EPO and erythropoietic stimulating agents into clinical practice has revolutionized the treatment of anemia despite certain concerns regarding the safety of the therapy. Recent studies demonstrate that EPO has activities in addition to hematopoiesis, and modulates bone remodeling by increasing bone resorption and decreasing bone formation, leading to trabecular bone loss. In vitro, EPO directly inhibits murine osteoblast differentiation and mineralization at doses relatively lower than those shown to stimulate osteoclastogenesis. The aim of this study was to investigate the dose-response relationship between EPO dose, hemoglobin (Hgb) levels, and the extent of bone loss, as well as to examine the role of the monocytic and B cell EPO receptor (EPOR) in bone metabolism. Results: Treating mice for 2 weeks with escalating doses of EPO, ranging from 6-540 IU/week, led to a dose-dependent increase in Hgb accompanied by a more dramatic decrease in trabecular bone mass; regression slopes of Hgb and bone volume/total volume (BV/TV, a measure of bone density) were 0.009 vs -0.09, respectively (p<0.05). These effects were associated with a significant increase in the number of preosteoclasts (CD115+ cells) in the bone marrow (r=0.74, p<0.05). To assess whether the osteoclast lineage contributes to EPO-induced bone loss, we generated mice lacking EPOR in the monocytic lineage (LysM-cre+/+;EPORflox/flox, cKO). At steady state, these mice and their LysM+/+;EPORwt/wt controls exhibited similar levels of Hgb (16.7±0.57 and 16.8 ±0.25 g/dL, respectively) and BV/TV (2.73%± 0.73 and 3.10%±0.76, respectively). Although not completely abolished, the bone loss induced by high EPO doses (540 IU/week) was significantly attenuated in cKO compared to control mice (60%±4.7 reduction versus 40%±13.2 reduction, respectively). At the same time, the levels of osteoclast precursors (CD115+ cells) increased from 3.08%±1.12 to 4.67%±0.92 in EPO-treated control mice, although there was no change in bone marrow preosteoclasts and preosteoblasts (defined as CD11b-/ALP+) in EPO-treated cKO mice. This suggests that osteoclast EPOR is responsible, at least in part, for mediating the effect of EPO on bone mass. Adding to the complexity of EPO's osteoimmunological roles, new findings suggest that EPO also regulates bone resorption via EPOR signaling in B cells. EPO stimulated surface expression of the osteoclastogenic RANKL in B cells (MFI: 2.6%±0.1 to 3.13%±0.09 P<0.05) and we found a higher bone mass in mice with conditional EPOR KO in B cells (MB1-cre+/-;EPORflox/flox) (vBMD, 52.2±15.1 versus 40.8±8.8 mg HA/cm3 in MB1-Cre+/-;EPORwt/wt, p<0.05). Conclusions: Our data demonstrate the complexity of EPO-induced bone loss mediated at least partly by EPOR signaling in both myeloid and B cell lineages. Furthermore, since patients who require treatment with EPO are prone to osteoporosis, our data suggest that using the lowest effective EPO dose would not only decrease the risk of thromboembolic complications but also minimize adverse skeletal outcomes. SHB and AK - Equal contribution; YG and DN - Equal contribution Funded by the German Israel Foundation, Grant # 01021017 to YG, DN, MR and BW and the Israel Science Foundation, Grant # 343/17 to DN. Disclosures No relevant conflicts of interest to declare.

scholarly journals B-Cell Deficiency Exacerbates Inflammation and Bone Loss in Ligature-Induced Experimental Periodontitis in Mice

2021 ◽  
Vol Volume 14 ◽  
pp. 5367-5380
Author(s):  
Wenmin Zeng ◽  
Guojing Liu ◽  
Qingxian Luan ◽  
Chunyu Yang ◽  
Shiyi Li ◽  
...  
Keyword(s):  
Bone Loss ◽  
B Cell ◽  
Experimental Periodontitis ◽  
B Cell Deficiency

scholarly journals B Cell IgD Deletion Prevents Alveolar Bone Loss Following Murine Oral Infection

2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
Author(s):  
Pamela J. Baker ◽  
Nicole Ryan Boutaugh ◽  
Michaela Tiffany ◽  
Derry C. Roopenian
Keyword(s):  
T Cells ◽  
B Cells ◽  
Bone Loss ◽  
B Cell ◽  
Tooth Loss ◽  
Alveolar Bone ◽  
Oral Infection ◽  
Alveolar Bone Loss ◽  
Oral Colonization ◽  
Deficient Mice

Periodontal disease is one of the most common infectious diseases of humans. Immune responses to infection trigger loss of alveolar bone from the jaw and eventual tooth loss. We investigated the contribution of B cell IgD to alveolar bone loss by comparing the response of B cell normal BALB/cJ mice and IgD deficient BALB/c-Igh-5−/−Jmice to oral infection withPorphyromonas gingivalis, a gram-negative periodontopathic bacterium from humans.P. gingivalis-infected normal mice lost bone. Specific antibody toP. gingivaliswas lower and oral colonization was higher in IgD deficient mice; yet bone loss was completely absent. Infection increased the proportion of CD69+activated B cells and CD4+T cells in immune normal mice compared to IgD deficient mice. These data suggest that IgD is an important mediator of alveolar bone resorption, possibly through antigen-specific coactivation of B cells and CD4+T cells.

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