scholarly journals The Non-Erythropoietic EPO Analogue (Cibinetide) Preserves Bone Mass in Mice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 850-850
Author(s):  
Zamzam Awida ◽  
Almog Bachar ◽  
Hussam Saed ◽  
Anton Gorodov ◽  
Nathalie Ben-Califa ◽  
...  
Keyword(s):  
Bone Loss ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Erythroid Progenitors ◽  
Mineral Density ◽  
Female Mice ◽  
Tissue Protection

Abstract Background and aims: Erythropoietin (EPO) is a pleiotropic cytokine, which besides its classical role in driving erythropoiesis, displays tissue protective and immunomodulatory activities. EPO also induces bone loss. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. Cibinetide (CIB), a non-erythropoietic analogue of EPO, specifically binds to the heteromeric receptor and confers tissue protection. Our published findings that EPO stimulates osteoclast precursors and entrains a decrease in bone density, raise questions regarding the underlying molecular mechanisms. Here, we evaluated the role of the heteromeric complex in bone metabolism using CIB alone and in combination with EPO in vivo and in vitro. Results: CIB injections to 12-week-old female mice (120 µg/kg thrice weekly for 4 weeks) resulted in a significant increase in tissue mineral density in cortical bone by 5.8% (1416.4±39.27 vs 1338.74±16.56 mgHA/cm 3) and in trabecular bone by 5.2% (1056.52±30.94 vs 1004.13±16.91 mg HA/cm 3) (n=10 in each group, p< 0.05 versus saline-injected controls), as measured by microCT (Figure 1A). To evaluate the capacity of CIB to attenuate EPO mediated bone loss, we administered CIB (300 µg/kg) for 5 consecutive days, to 13-week-old female mice that also received 2 injections of 120U EPO on days 1 and 4. Flow cytometry analysis revealed a 1.8-fold reduction in the number of osteoclast progenitors, defined as Lin -CD11b −CD115 +Ly6C hi, in the EPO + CIB injected mice, compared to the mice injected with EPO alone (n=7 in each group, p< 0.05). Hemoglobin levels and TER119 + bone marrow (BM) erythroid progenitors were similar in both groups. In vitro, EPO administration to BM-derived macrophages (BMDM) enhanced osteoclastogenesis, whereas CIB had an opposite, dose-dependent effect. Combining CIB with EPO inhibited osteoclastogenesis in BMDM, suggesting that CIB overrides the pro-osteoclastogenic effect of EPO (Figure 1B). Conclusions: Our findings highlight the increasing complexity of EPOR signaling in bone and pave the way for clinical translation through potential combination therapy of EPO and CIB in anemic and in cancer patients. Adjunctive administration of CIB may prevent or attenuate bone loss while preserving the erythropoietic actions of EPO. This study was supported by a grant from the Dotan Hemato-oncology Fund, the Cancer Biology Research Center, Tel Aviv University to DN and YG. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice

2021 ◽  
Vol 23 (1) ◽  
pp. 55
Author(s):  
Zamzam Awida ◽  
Almog Bachar ◽  
Hussam Saed ◽  
Anton Gorodov ◽  
Nathalie Ben-Califa ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Loss ◽  
Bone Mineral ◽  
Molecular Mechanisms ◽  
Mineral Density ◽  
Female Mice ◽  
Epo Receptor

The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin−CD11b−Ly6Chi CD115+, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.

scholarly journals Protective Effects of Water Extract of Fructus Ligustri Lucidi against Oxidative Stress-Related Osteoporosis In Vivo and In Vitro

2021 ◽  
Vol 8 (9) ◽  
pp. 198
Author(s):  
Yi Wu ◽  
Yusheng Hu ◽  
Zeguang Zhao ◽  
Lina Xu ◽  
Ye Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Loss ◽  
Water Extract ◽  
Mineral Density ◽  
Female Mice ◽  
Fructus Ligustri Lucidi ◽  
Low Calcium Diet ◽  
Low Calcium

Fructus Ligustri Lucidi (FLL) is the fruit of Ligustrum lucidum Ait and is a component of many kidney-tonifying traditional Chinese medicine formulae for treating osteoporosis. Accumulating evidence has linked oxidative stress with the progression of bone diseases. The present study aimed to identify the effects of FLL on oxidative stress-related osteoporosis in vivo and in vitro. To construct animal models, we utilized d-galactose (D-gal) injection to induce oxidative stress combined with a low calcium (the exact percentage in the diet was 0.1%) diet. Thirteen-week-old Kunming female mice were gavaged with water extract of FLL for 20 days. Then, eight-month-old Kunming female mice were treated with FLL under standard administration and diet as the aged group. In vitro, MC3T3-E1 cells stimulated by H2O2 were treated with FLL for 24 h. The micro-CT results showed that the modeling approach combining oxidative stress with a low calcium diet caused low conversion type osteoporosis in mice. FLL exerted a prominent effect on preventing osteoporosis by inhibiting oxidative stress, increasing bone mineral density (BMD), improving bone microstructure, and promoting osteoblast proliferation and osteoprotegerin (OPG) protein expression; however, FLL had no therapeutic effect on bone loss in aged mice. In conclusion, FLL showed outstanding anti-bone loss ability both in vivo and in vitro and could probably be developed as a prophylactic agent for osteoporosis.

scholarly journals Crataegus pinnatifida Bunge Inhibits RANKL-Induced Osteoclast Differentiation in RAW 264.7 Cells and Prevents Bone Loss in an Ovariectomized Rat Model

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Minsun Kim ◽  
MinBeom Kim ◽  
Jae-Hyun Kim ◽  
SooYeon Hong ◽  
Dong Hee Kim ◽  
...  
Keyword(s):  
Bone Loss ◽  
Rat Model ◽  
Osteoclast Differentiation ◽  
Ovariectomized Rat ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Mineral Density ◽  
Crataegus Pinnatifida

Osteoporosis is characterized by a decrease in bone microarchitecture with an increased risk of fracture. Long-term use of primary treatments, such as bisphosphonates and selective estrogen receptor modulators, results in various side effects. Therefore, it is necessary to develop alternative therapeutics derived from natural products. Crataegus pinnatifida Bunge (CPB) is a dried fruit used to treat diet-induced indigestion, loss of appetite, and diarrhea. However, research into the effects of CPB on osteoclast differentiation and osteoporosis is still limited. In vitro experiments were conducted to examine the effects of CPB on RANKL-induced osteoclast differentiation in RAW 264.7 cells. Moreover, we investigated the effects of CPB on bone loss in the femoral head in an ovariectomized rat model using microcomputed tomography. In vitro, tartrate-resistant acid phosphatase (TRAP) staining results showed the number of TRAP-positive cells, and TRAP activity significantly decreased following CPB treatment. CPB also significantly decreased pit formation. Furthermore, CPB inhibited osteoclast differentiation by suppressing NFATc1, and c-Fos expression. Moreover, CPB treatment inhibited osteoclast-related genes, such as Nfatc1, Ca2, Acp5, mmp9, CtsK, Oscar, and Atp6v0d2. In vivo, bone mineral density and structure model index were improved by administration of CPB. In conclusion, CPB prevented osteoclast differentiation in vitro and prevented bone loss in vivo. Therefore, CPB could be a potential alternative medicine for bone diseases, such as osteoporosis.

scholarly journals Fucoidan Prevents RANKL-Stimulated Osteoclastogenesis and LPS-Induced Inflammatory Bone Loss via Regulation of Akt/GSK3β/PTEN/NFATc1 Signaling Pathway and Calcineurin Activity

Marine Drugs ◽  
2019 ◽  
Vol 17 (6) ◽  
pp. 345 ◽  
Author(s):  
Sheng-Hua Lu ◽  
Yi-Jan Hsia ◽  
Kuang-Chung Shih ◽  
Tz-Chong Chou
Keyword(s):  
Bone Loss ◽  
Molecular Mechanisms ◽  
Bone Erosion ◽  
Osteoclast Differentiation ◽  
Bone Diseases ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Calcineurin Activity

Excessive osteoclast differentiation and/or function plays a pivotal role in the pathogenesis of bone diseases such as osteoporosis and rheumatoid arthritis. Here, we examined whether fucoidan, a sulfated polysaccharide present in brown algae, attenuates receptor activator of nuclear factor-κB ligand (RANKL)-stimulated osteoclastogenesis in vitro and lipopolysaccharide (LPS)-induced bone resorption in vivo, and investigated the molecular mechanisms involved. Our results indicated that fucoidan significantly inhibited osteoclast differentiation in RANKL-stimulated macrophages and the bone resorbing activity of osteoclasts. The effects of fucoidan may be mediated by regulation of Akt/GSK3β/PTEN signaling and suppression of the increase in intracellular Ca2+ level and calcineurin activity, thereby inhibiting the translocation of nuclear factor-activated T cells c1 (NFATc1) into the nucleus. However, fucoidan-mediated NFATc1 inactivation was greatly reversed by kenpaullone, a GSK3β inhibitor. In addition, using microcomputer tomography (micro-CT) scanning and bone histomorphometry, we found that fucoidan treatment markedly prevented LPS-induced bone erosion in mice. Collectively, we demonstrated that fucoidan was capable of inhibiting osteoclast differentiation and inflammatory bone loss, which may be modulated by regulation of Akt/GSK3β/PTEN/NFATc1 and Ca2+/calcineurin signaling cascades. These findings suggest that fucoidan may be a potential agent for the treatment of osteoclast-related bone diseases.

A NUP98-HOXD13 Leukemic Fusion Gene Leads To Aberrant Actin Localization In Dysplastic Megakaryocytes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2486-2486
Author(s):  
David L. Caudell ◽  
Benjamin Okyere ◽  
Jacob Cawley ◽  
Abdul Gafoor A. Puthiyaveetil ◽  
Bettina Heid
Keyword(s):  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Hematopoietic Malignancy ◽  
Glass Slides ◽  
Transmission Electron ◽  
Platelet Release ◽  
Actin Localization

Abstract Myelodysplastic syndrome (MDS) is a hematopoietic malignancy characterized by peripheral cytopenias due to bone marrow (BM) failure. Megakarypoiesis, megakaryocyte (MK) production, and platelet release are impaired in in some cases of MDS. Patients often have fewer, but larger circulating platelets, which have abnormal demarcation membrane systems (DMS); the DMS, which determines the number and size of platelets released, is dependent on actin formation. However, the precise role of actin during megakaryopoiesis is poorly understood. Transgenic mice that express the fusion gene NUP98-HOXD13 (NHD13) is a model for MDS and have dysplastic MKs in BM, and macro platelets in circulation. We hypothesized that expression of NHD13 disrupts actin localization during megakaryopoiesis resulting in reduced platelet release and macro platelet formation. To test the hypothesis, BM from wild type (WT) and NHD13 mice were flushed and cultured in media supplemented with Thrombopoietin for 5 days. Following in vitro propagation, MKs were harvested over a discontinuous gradient for downstream experiments. Sternums were also fixed in paraformaldehyde, stained with hematoxylin and eosin, and evaluated by light microscopy to analyze MK morphology in vivo. NHD13 BM contained many dysplastic MKs. Harvested MKs and BM cores from one femur were processed and analyzed by transmission electron microscopy (TEM) and the ultrastructural properties of the DMS detailed. TEM of MKs showed NHD13 leads to formation of an irregular DMS along with abnormal distribution of unusually large granules in MK cytoplasm. Cultured MKs were also cytospun onto glass slides, labeled with fluorescent-tagged F-actin and Myosin IIa and the cytoskeleton visualized by confocal microscopy. WT MKs in vitro had two phenotypes: (1) MKs with myosin and actin evenly dispersed in the cytoplasm and (2) MK with actin predominantly in the periphery of the cytoplasm. In contrast, transgenic MKs displayed only the former phenotype suggesting that actin localization is impaired in NHD13 MKs. Finally, MKs were stimulated with estrogen and adhered to fibrinogen matrices to determine their proplatelet formation functionality. Our results showed impaired proplatelets formation in NHD13 MKs. These data suggest that expression of NHD13 leads to aberrant actin localization leading to dysplastic MK differentiation and macro platelet release. Understanding molecular mechanisms of abnormal megakaryopoiesis in MDS is important as many MDS patients die of hemorrhagic complications. Further studies using this model system will provide a platform for translational research and should reveal potential therapeutic targets in MDS, leading to improved patient care/survival. Disclosures: No relevant conflicts of interest to declare.

Identification and Functional Characterization of Metabolites for Bone Mass in Peri-/Post-menopausal Chinese Women

2021 ◽  
Author(s):  
Rui Gong ◽  
Hong-Mei Xiao ◽  
Yin-Hua Zhang ◽  
Qi Zhao ◽  
Kuan-Jui Su ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Bone Loss ◽  
Osteoclast Differentiation ◽  
Dodecanoic Acid ◽  
Mineral Density ◽  
Ovariectomized Mice ◽  
Post Menopausal ◽  
Functional Mechanisms

Abstract Context Although metabolic profiles appear to play an important role in menopausal bone loss, the functional mechanisms by which metabolites influence bone mineral density (BMD) during menopause are largely unknown. Objective We aimed to systematically identify metabolites associated with BMD variation and their potential functional mechanisms in peri-/post-menopausal women. Design and Methods We performed serum metabolomic profiling and whole-genome sequencing for 517 perimenopausal (16%) and early postmenopausal (84%) women aged 41 to 64 years in this cross-sectional study. Partial least squares (PLS) regression and general linear regression analysis were applied to identify BMD-associated metabolites, and weighted gene co-expression network analysis was performed to construct co-functional metabolite modules. Furthermore, we performed Mendelian randomization analysis to identify causal relationships between BMD-associated metabolites and BMD variation. Finally, we explored the effects of a novel prominent BMD-associated metabolite on bone metabolism through both in vivo/in vitro experiments. Results Twenty metabolites and a co-functional metabolite module (consisting of fatty acids) were significantly associated with BMD variation. We found dodecanoic acid (DA), within the identified module, causally decreased total hip BMD. Subsequently, the in vivo experiments might support that dietary supplementation with DA could promote bone loss, as well as increase the osteoblast and osteoclast numbers in normal/ovariectomized mice. DA treatment differentially promoted osteoblast and osteoclast differentiation, especially for osteoclast differentiation at higher concentrations in vitro (e.g.,10, 100μM). Conclusions This study sheds light on metabolomic profiles associated with postmenopausal osteoporosis risk, highlighting the potential importance of fatty acids, as exemplified by DA, in regulating BMD.

Lycorine Modulates the Expression of p21 Via a p53-Independent Pathway in HL-60 Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4297-4297
Author(s):  
Jing Liu ◽  
Shu-Ling Wang ◽  
Lin Fang ◽  
Mao Ye ◽  
Zhi-Wei Sun ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Fold Increase ◽  
Alternative Pathways ◽  
Cyclin Dependent Kinase Inhibitor ◽  
M Phase ◽  
Induced Apoptosis

Abstract Abstract 4297 Leukemia is one of the most life-threatening cancers today, and acute promyelogenous leukemia is a common type of leukemia. We have previously shown that lycorine, a natural alkaloid extract from Amaryllidaceae, exhibited anti-leukemia effects in vitro and in vivo. Lycorine treatment of HL-60 cell arrested cell cycle at G2/M phase and induced apoptosis. In the present study, we sought to explore the molecular mechanisms for the anti-leukemia action of lycorine. Gene chip analysis revealed that lycorine treatment of HL-60 cells induced more than 9 fold increase of p21, a cyclin-dependent kinase inhibitor, whose expression is mainly regulated by p53. Since HL-60 cells are p53 null, the above findings suggest that lycorine activates p21 expression through p53-independent pathway. To further explore the alternative pathways for the activation of p21 induced by lycorine, we examined the effect of lycorine on the expression of Rb, pRb, E2F, c-Myc and HDACs which have shown to regulate p21 expression. We show that expression of pRb (ser780) and c-Myc was down-regulated, Rb and E2F were up-regulated, while the expression of HDAC1 and HDAC3 was not changed. Together these findings suggest that lycorine exerts its anti-leukemia effect by activating p21 expression via pRb/E2F and c-Myc pathways. Disclosures: No relevant conflicts of interest to declare.

Expression Of Mutant Spliceosomal Protein SF3B1 Results In Dysregulated Hematopoietic Maturation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2773-2773
Author(s):  
Alexander C. Minella ◽  
Oscar Ramirez ◽  
Yanfei Xu ◽  
Tushar Murthy ◽  
Xiaodong Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Erythroid Differentiation ◽  
Retroviral Vectors ◽  
Peptide Sequence ◽  
Causative Role ◽  
Wild Type ◽  
Erythroid Maturation

Abstract Whole genome sequencing has recently revealed the prevalence of mutations in proteins directing splicing of RNA in up to half of the patients with Myelodysplastic Syndrome (MDS). Mutations in the protein SF3B1 are particularly common in MDS patients with the phenotypic abnormality termed ring sideroblasts (dysplastic erythroid precursors with perinculear rings formed by iron-laden mitochondria). The most common SF3B1 mutation in MDS patients results in a change from lysine to glutamic acid at amino acid position 700 (K700E). Given that splicing of RNA is a ubiquitous phenomenon, it is unclear how these mutations result in clonal proliferation and dysplastic hematopoiesis; two hallmark features of MDS. Furthermore, direct experimental evidence demonstrating a causative role for SF3B1 mutations in MDS-related phenotypes is lacking. To better understand how mutations of spliceosomal proteins contribute to MDS pathogenesis, we sought to define how expression of mutant SF3B1 changes erythroid maturation in vitro and in vivo. Native SF3B1 cDNA constructs are not amenable to bacterial propagation due to toxicity of its HEAT-domain repeats. We overcame this problem by codon optimization (changing the DNA sequence while preserving the native peptide sequence). Human cord blood derived CD34+ cells were transduced with retroviral vectors to express either the wild-type or K700E mutant of SF3B1. After a week of expansion in cytokines (IL-3, SCF and IL6), cells were induced to erythroid differentiation by addition of erythropoietin (EPO) and analyzed for surface markers of erythroid differentiation (CD 71, CD117, CD105, CD45 and CD235A) at regular intervals. K700E mutant expressing cells were found to have significantly reduced expression of CD105 when compared to wild-type SF3B1-expressing cells (average 50% recuction, n =8). CD105 or endoglin is a TGF-beta receptor accessory receptor expressed at high levels during intermediate stages of erythroid maturation. A more modest reduction of CD71 expression was also noted in K700E-SF3B1 cells. MDS bone marrow is known to express low levels of both CD105 and CD71 making our results clinically relevant. To further characterize how mutant SF3B1 may cause dysplastic hematopoiesis, we studied transduced and transplanted murine progenitor cells in vivo and in colony forming assays. Murine data demonstrate significantly reduced K700E-transduced hematopoietic progenitors (as defined by flow-cytometry) in vivo and impaired erythroid colony formation in vitro. Together, our results suggest that enforced expression of K700E-SF3B1 induces aberrant erythroid maturation and impairs homeostasis of hematopoietic precursor cells. Thus, we provide direct evidence that MDS-associated SF3B1 mutations perturb normal hematopoiesis and offer rationale for using our complementary experimental approach as a platform for elucidating the molecular mechanisms through which mutations in RNA splicing factors promote hematologic disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Osteoporosis Recovery byAntrodia camphorataAlcohol Extracts through Bone Regeneration in SAMP8 Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Hen-Yu Liu ◽  
Chiung-Fang Huang ◽  
Chun-Hao Li ◽  
Ching-Yu Tsai ◽  
Wei-Hong Chen ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Matrix ◽  
Mineral Density ◽  
Antrodia Camphorata ◽  
Osteoporosis Therapy ◽  
Alizarin Red ◽  
Alcohol Extract ◽  
Samp8 Mice

Antrodia camphoratahas previously demonstrated the efficacy in treating cancer and anti-inflammation. In this study, we are the first to evaluateAntrodia camphorataalcohol extract (ACAE) for osteoporosis recoveryin vitrowith preosteoblast cells (MC3T3-E1) andin vivowith an osteoporosis mouse model established in our previous studies, ovariectomized senescence accelerated mice (OVX-SAMP8). Our results demonstrated that ACAE treatment was slightly cytotoxic to preosteoblast at 25 μg/mL, by which the osteogenic gene expression (RUNX2, OPN, and OCN) was significantly upregulated with an increased ratio of OPG to RANKL, indicating maintenance of the bone matrix through inhibition of osteoclastic pathway. Additionally, evaluation by Alizarin Red S staining showed increased mineralization in ACAE-treated preosteoblasts. Forin vivostudy, our results indicated that ACAE inhibits bone loss and significantly increases percentage bone volume, trabecular bone number, and bone mineral density in OVX-SAMP8 mice treated with ACAE. Collectively,in vitroandin vivoresults showed that ACAE could promote osteogenesis and prevent bone loss and should be considered an evidence-based complementary and alternative medicine for osteoporosis therapy through the maintenance of bone health.

scholarly journals Anti–IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss

2011 ◽  
Vol 208 (9) ◽  
pp. 1849-1861 ◽  
Author(s):  
Yu-Hsiang Hsu ◽  
Wei-Yu Chen ◽  
Chien-Hui Chan ◽  
Chih-Hsing Wu ◽  
Zih-Jie Sun ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Loss ◽  
Therapeutic Potential ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Osteoporotic Bone ◽  
Mineral Density

IL-20 is a proinflammatory cytokine of the IL-10 family that is involved in psoriasis, rheumatoid arthritis, atherosclerosis, and stroke. However, little is known about the role of IL-20 in bone destruction. We explored the function of IL-20 in osteoclastogenesis and the therapeutic potential of anti–IL-20 monoclonal antibody 7E for treating osteoporosis. Higher serum IL-20 levels were detected in patients with osteopenia and osteoporosis and in ovariectomized (OVX) mice. IL-20 mediates osteoclastogenesis by up-regulating the receptor activator of NF-κB (RANK) expression in osteoclast precursor cells and RANK ligand (RANKL) in osteoblasts. 7E treatment completely inhibited osteoclast differentiation induced by macrophage colony-stimulating factor (M-CSF) and RANKL in vitro and protected mice from OVX-induced bone loss in vivo. Furthermore, IL-20R1–deficient mice had significantly higher bone mineral density (BMD) than did wild-type controls. IL-20R1 deficiency also abolished IL-20–induced osteoclastogenesis and increased BMD in OVX mice. We have identified a pivotal role of IL-20 in osteoclast differentiation, and we conclude that anti–IL-20 monoclonal antibody is a potential therapeutic for protecting against osteoporotic bone loss.

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