IGF-binding protein-5 stimulates osteoblast activity and bone accretion in ovariectomized mice

2001 ◽  
Vol 281 (2) ◽  
pp. E283-E288 ◽  
Author(s):  
Dennis L. Andress
Keyword(s):  
Bone Formation ◽  
Binding Protein ◽  
Formation Rate ◽  
Bone Matrix ◽  
Secretory Protein ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Ovariectomized Mice ◽  
Osteoblast Activity

Insulin-like growth factor binding protein-5 (IGFBP-5) is an osteoblast secretory protein that becomes incorporated into the mineralized bone matrix. In osteoblast cultures, IGFBP-5 stimulates cell proliferation by an IGF-independent mechanism. To evaluate whether IGFBP-5 can stimulate osteoblast activity and enhance bone accretion in a mouse model of osteoblast insufficiency, daily subcutaneous injections of either intact [IGFBP-5 (intact)] or carboxy-truncated IGFBP-5 [IGFBP-5-(1–169)] were given to ovariectomized (OVX) mice for 8 wk. Femur and spine bone mineral density (BMD), measured every 2 wk, showed early and sustained increases in response to IGFBP-5. Bone histomorphometry of cancellous bone showed significant elevations in the bone formation rate in both the femur metaphysis [IGFBP-5- (1)] only) and spine compared with OVX controls. IGFBP-5 also stimulated osteoblast number in the femur IGFBP-5-(1–169) only) and spine. These data indicate that IGFBP-5 effectively enhances bone formation and bone accretion in OVX mice by stimulating osteoblast activity. The finding that IGFBP-5-(1–169) is bioactive in vivo indicates that the carboxy-terminal portion is not required for this bone anabolic effect.

1,25(OH)2D3 acts as a bone-forming agent in the hormone-independent senescence-accelerated mouse (SAM-P/6)

2005 ◽  
Vol 288 (4) ◽  
pp. E723-E730 ◽  
Author(s):  
Gustavo Duque ◽  
Michael Macoritto ◽  
Natalie Dion ◽  
Louis-Georges Ste-Marie ◽  
Richard Kremer
Keyword(s):  
Bone Formation ◽  
Bone Turnover ◽  
Bone Marrow Cells ◽  
Formation Rate ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Senile Osteoporosis ◽  
Dihydroxyvitamin D ◽  
Bone Formation Markers

Recent studies suggest that vitamin D signaling regulates bone formation. However, the overall effect of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on bone turnover in vivo is still unclear. In this study, our aim was to examine the effect of 1,25(OH)2D3 on bone turnover in SAM-P/6, a hormone-independent mouse model of senile osteoporosis characterized by a decrease in bone formation. Male and female 4-mo-old SAM-P/6 mice were treated with 1,25(OH)2D3 (18 pmol/24 h) or vehicle for a period of 6 wk, and a group of age- and sex-matched nonosteoporotic animals was used as control. Bone mineral density (BMD) at the lumbar spine increased rapidly by >30 ± 5% ( P < 0.001) in 1,25(OH)2D3-treated SAM-P/6 animals, whereas BMD decreased significantly by 18 ± 2% ( P < 0.01) in vehicle-treated SAM-P/6 animals and remained stable in control animals during the same period. Static and dynamic bone histomorphometry indicated that 1,25(OH)2D3 significantly increased bone volume and other parameters of bone quality as well as subperiosteal bone formation rate compared with vehicle-treated SAM-P/6 mice. However, no effect on trabecular bone formation was observed. This was accompanied by a marked decrease in the number of osteoclasts and eroded surfaces. A significant increase in circulating bone formation markers and a decrease in bone resorption markers was also observed. Finally, bone marrow cells, obtained from 1,25(OH)2D3-treated animals and cultured in the absence of 1,25(OH)2D3, differentiated more intensely into osteoblasts compared with those derived from vehicle-treated mice cultured in the same conditions. Taken together, these findings demonstrate that 1,25(OH)2D3 acts simultaneously on bone formation and resorption to prevent the development of senile osteoporosis.

scholarly journals Bone Histomorphometry in Children and Adolescents with β-Thalassemia Disease: Iron-Associated Focal Osteomalacia

2003 ◽  
Vol 88 (8) ◽  
pp. 3966-3972 ◽  
Author(s):  
Pat Mahachoklertwattana ◽  
Vorachai Sirikulchayanonta ◽  
Ampaiwan Chuansumrit ◽  
Patcharee Karnsombat ◽  
Lulin Choubtum ◽  
...  
Keyword(s):  
Bone Formation ◽  
Children And Adolescents ◽  
Bone Histomorphometry ◽  
Bone Biopsy ◽  
Formation Rate ◽  
Bone Matrix ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Igf I ◽  
Iron Deposits

Thalassemia/hemoglobinopathy is a hereditary disease that causes chronic anemia and increased erythropoiesis. Consequently, an expansion of bone marrow spaces may contribute to osteopenia/osteoporosis. However, the pathogenesis of bone changes is not yet known. We, therefore, carried out the study on bone histomorphometry and biochemical and hormonal profiles in children and adolescents with suboptimally treated β-thalassemia disease with the hope of gaining some new insight into the cellular and structural alterations of thalassemic bone. Seventeen patients underwent iliac crest bone biopsy for histomorphometric analyses. Bone mineral density (BMD) measurements were performed by dual energy x-ray absorptiometry. Most patients had growth retardation and delayed bone age. BMD was low especially at the lumbar spine. Serum IGF-I levels were almost always low. Bone histomorphometry revealed increased osteoid thickness, osteoid maturation time, and mineralization lag time, which indicate impaired bone matrix maturation and defective mineralization. In addition, iron deposits appeared along mineralization fronts and osteoid surfaces. Moreover, focal thickened osteoid seams were found together with focal iron deposits. Dynamic bone formation study revealed reduced bone formation rate. These findings indicate that delayed bone maturation and focal osteomalacia are the pathogenesis of bone disease in suboptimally blood-transfused thalassemics with iron overload. Iron deposits in bone and low circulating IGF-I levels may partly contribute to the above findings.

Regulation of bone repletion in rats subjected to varying low-calcium stress

1984 ◽  
Vol 246 (2) ◽  
pp. R190-R196 ◽  
Author(s):  
R. H. Drivdahl ◽  
C. C. Liu ◽  
D. J. Baylink
Keyword(s):  
Bone Formation ◽  
Formation Rate ◽  
Bone Volume ◽  
Strong Positive Correlation ◽  
Sprague Dawley ◽  
Bone Formation Rate ◽  
Osteoblast Activity ◽  
Calcium Stress ◽  
Sprague Dawley Rats ◽  
Very High

Weanling Sprague-Dawley rats subjected to varying degrees of low-Ca dietary stress (depletion) showed graded increases in the rate of endosteal bone formation when normal dietary Ca was restored (repletion). There was a strong positive correlation between the rate of bone resorption in depletion and the rate of bone formation attained after 1 wk of repletion. However, bone formation declined rapidly within the first 4 wk of repletion, despite the persistence of a substantial endosteal bone volume deficit. Furthermore the medullary area (indicative of bone volume) did not by itself determine the bone formation rate. Bone volume in test groups was restored to control levels after 6 mo of repletion, and this result could be predicted by a kinetic analysis. Thus, although very high rates of formation in early repletion decline rapidly, smaller increments relative to controls must be sustained for long periods. Our data indicate that increased formation rats at all stages of repletion are a consequence of elevations in both osteoblast number and osteoblast activity.

Bone modeling in bromocriptine-treated pregnant and lactating rats: possible osteoregulatory role of prolactin in lactation

2010 ◽  
Vol 299 (3) ◽  
pp. E426-E436 ◽  
Author(s):  
Panan Suntornsaratoon ◽  
Kannikar Wongdee ◽  
Suchandra Goswami ◽  
Nateetip Krishnamra ◽  
Narattaphol Charoenphandhu
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Trabecular Bone ◽  
Formation Rate ◽  
Bone Modeling ◽  
Mineral Density ◽  
Pregnant Rats ◽  
Bone Formation Rate ◽  
Bone Trabeculae ◽  
Bone Gain

The lactogenic hormone prolactin (PRL) directly regulates osteoblast functions in vitro and modulates bone remodeling in nulliparous rats, but its osteoregulatory roles in pregnant and lactating rats with physiological hyperprolactinemia remained unclear. Herein, bone changes were investigated in rats treated with bromocriptine (Bromo), an inhibitor of pituitary PRL release, or Bromo+PRL at different reproductive phases, from mid-pregnancy to late lactation. PRL receptors were strongly expressed in osteoblasts lining bone trabeculae, indicating bone as a target of PRL actions. By using dual energy X-ray absorptiometry, we found a significant increase in bone mineral density in the femora and vertebrae of pregnant rats. Such pregnancy-induced bone gain was, however, PRL independent and may have resulted from the increased cortical thickness. Bone trabeculae were modestly changed during pregnancy as evaluated by bone histomorphometry. On the other hand, lactating rats, especially in late lactation, showed massive bone loss in bone trabeculae but not in cortical shells. Further study in Bromo- and Bromo+PRL-treated rats suggested that PRL contributed to decreases in trabecular bone volume and number and increases in trabecular separation and eroded surface, as well as a paradoxical increase in bone formation rate in late lactation. Uncoupling of trabecular bone formation and resorption was evident in lactating rats, with the latter being predominant. In conclusion, pregnancy mainly induced cortical bone gain, whereas lactation led to trabecular bone loss in both long bones and vertebrae. Although PRL was not responsible for the pregnancy-induced bone gain, it was an important regulator of bone modeling during lactation.

scholarly journals New Bone Formation with Teriparatide [Human Parathyroid Hormone-(1–34)] Is Not Retarded by Long-Term Pretreatment with Alendronate, Estrogen, or Raloxifene in Ovariectomized Rats

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 2008-2015 ◽  
Author(s):  
Yanfei L. Ma ◽  
Henry U. Bryant ◽  
Qingqiang Zeng ◽  
Allen Schmidt ◽  
Jennifer Hoover ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Formation Rate ◽  
Prior Exposure ◽  
Ovariectomized Rats ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Teriparatide Treatment ◽  
Antiresorptive Agents ◽  
Ovx Rats

With the ready availability of several osteoporosis therapies, teriparatide [human PTH-(1–34)] is likely to be prescribed to postmenopausal women with prior exposure to agents that prevent bone loss, such as bisphosphonates, estrogen, or selective estrogen receptor modulators. Therefore, we evaluated the ability of once daily teriparatide to induce bone formation in ovariectomized (Ovx) rats with extended prior exposure to various antiresorptive agents, such as alendronate (ABP), 17α-ethinyl estradiol (EE), or raloxifene (Ral). Sprague Dawley rats were Ovx and treated with ABP (28 μg/kg, twice weekly), EE (0.1 mg/kg·d), or Ral (1 mg/kg·d) for 10 months before switching to teriparatide 30 μg/kg·d for another 2 months. Analysis of the proximal tibial metaphysis showed that all three antiresorptive agents prevented ovariectomy-induced bone loss after 10 months, but were mechanistically distinct, as shown by histomorphometry. Before teriparatide treatment, ABP strongly suppressed activation frequency and bone formation rate to below levels in other treatment groups, whereas these parameters were not different from sham values for EE or Ral. Trabecular area for ABP, EE, and Ral were greater than that in Ovx controls. However, the trabecular bone effects of ABP were attributed not only to effects on the secondary spongiosa, but also to the preservation of primary spongiosa, which was prevented from remodeling. After 2 months of teriparatide treatment, lumbar vertebra showed relative bone mineral density increases of 18%, 7%, 11%, and 10% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Histomorphometry showed that trabecular area was increased by 105%, 113%, 36%, and 48% for vehicle/teriparatide, ABP/teriparatide, EE/teriparatide, and Ral/teriparatide, respectively, compared with 10 month levels. Teriparatide enhanced mineralizing surface, mineral apposition rate, and bone formation rate in all groups. Compression testing of vertebra showed that teriparatide improved strength (peak load) and toughness in all groups to a proportionately similar extent compared with 10 month levels. These data showed a surprising ability of the rat skeleton to respond to teriparatide despite extensive pretreatment with ABP, EE, or Ral. Therefore, the mature skeleton of Ovx rats remains highly responsive to the appositional effects of teriparatide regardless of pretreatment status in terms of cancellous bone area or rate of bone turnover.

Anti-Myeloma Response to Bortezomib Is Associated with Increased Osteoblast Activity and Bone Formation in Primary Myelomatous SCID-rab Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3450-3450
Author(s):  
Shmuel Yaccoby ◽  
Wen Ling ◽  
Rinku Saha ◽  
Bart Barlogie ◽  
Guido Tricot ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mineral ◽  
Ex Vivo ◽  
Experimental Period ◽  
Bone Alkaline Phosphatase ◽  
X Rays ◽  
Mineral Density ◽  
Osteoblast Activity ◽  
Osteolytic Bone Disease

Abstract Recent studies have indicated that certain proteasome inhibitors have bone anabolic activity in vivo. Our clinical study have shown a significant association between anti-myeloma (MM) response of bortezomib (Millennium Pharmaceuticals) and increased serum bone alkaline phosphatase in patients with MM (Zangari et al., BJH 2005, In press). The aim of this study was to investigate the effect of bortezomib on bone remodeling and the association between anti-myeloma response and increased bone formation in our established SCID-rab model for primary MM. In this system rabbit bones were implanted S.C. in unconditioned SCID mice. After 6 weeks, primary MM cells were injected directly into the implanted bone. MM cells from &gt;85% of patients (n&gt;70) were successfully engrafted, grew exclusively in the implanted bone and produced typical disease manifestations including increased osteoclast activity, reduced osteoblast numbers and induction of osteolytic bone disease (Yata & Yaccoby, Leukemia 2004). In the present study, SCID-rab mice were engrafted with MM cells from 5 patients. Following establishment of MM growth, as monitored by weekly measurement of human monoclonal immunoglobulins (hIg) in mice sera (587±276 μg/ml) and by x-rays, mice were injected subcutaneously twice a week with 0.5 mg/kg bortezomib or PBS for 4–8 weeks. Whereas all PBS-treated mice had increased hIg levels during the experimental period, bortezomib treatment resulted in marked reduction of hIg in 2 experiments by 95% and 73% from pretreatment levels, respectively, retardation of myeloma growth in an additional experiment and no response in 2 experiments. Overall, tumor burden in control PBS- and bortezomib-treated mice was increased by 298%±51 and 110%±88 from pretreatment levels, respectively (p&lt;0.03). In control mice the implanted rabbit bone mineral density (BMD) and bone mineral content (BMC) were reduced by 23%±6% and 27%±10% from pretreatment levels, respectively, whereas in bortezomib-responsive mice BMD and BMC were increased by 57%±23% and 79%±60% from pretreatment levels, respectively (p&lt;0.05, bortezomib vs. PBS). In the 2 non-responsive mice BMD and BMC were reduced by 36%±7% and 40%±3% from pretreatment levels, respectively, similar to the matched control mice. The bone anabolic effect of bortezomib could also be visualized on x-rays. Histological examination of a bone from a responsive myeloma revealed increased numbers of osteocalcin-expressing osteoblasts (25±4 vs. 8±3 per mm bone in control mice, p&lt;0.03) and reduced number of multinucleated TRAP-expressing multinucleated osteoclasts (59±6 vs. 20±4 per mm bone in control mice, p&lt;0.008). We conclude that anti-myeloma response to bortezomib is associated with increased osteoblast activity and bone formation in myelomatous bone. Since we previously demonstrated the ability of osteoblasts to inhibit growth of primary MM cells ex vivo, our study suggests an additional mechanism by which bortezomib inhibits myeloma.

scholarly journals Bone microstructural defects and osteopenia in hemizygous βIVSII-654knockin thalassemic mice: sex-dependent changes in bone density and osteoclast function

2015 ◽  
Vol 309 (11) ◽  
pp. E936-E948 ◽  
Author(s):  
Kanogwun Thongchote ◽  
Saovaros Svasti ◽  
Jarinthorn Teerapornpuntakit ◽  
Panan Suntornsaratoon ◽  
Nateetip Krishnamra ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Histomorphometry ◽  
Formation Rate ◽  
Computer Assisted ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Male And Female ◽  
Female Mice ◽  
Growing Period ◽  
Microstructural Defects

β-Thalassemia, a hereditary anemic disorder, is often associated with skeletal complications that can be found in both males and females. The present study aimed to investigate the age- and sex-dependent changes in bone mineral density (BMD) and trabecular microstructure in βIVSII-654knockin thalassemic mice. Dual-energy X-ray absorptiometry and computer-assisted bone histomorphometry were employed to investigate temporal changes in BMD and histomorphometric parameters in male and female mice of a βIVSII-654knockin mouse model of human β-thalassemia, in which impaired splicing of β-globin transcript was caused by hemizygous C→T mutation at nucleotide 654 of intron 2. Young, growing βIVSII-654mice (1 mo old) manifested shorter bone length and lower BMD than their wild-type littermates, indicating possible growth retardation and osteopenia, the latter of which persisted until 8 mo of age (adult mice). Interestingly, two-way analysis of variance suggested an interaction between sex and βIVSII-654genotype, i.e., more severe osteopenia in adult female mice. Bone histomorphometry further suggested that low trabecular bone volume in male βIVSII-654mice, particularly during a growing period (1–2 mo), was primarily due to suppression of bone formation, whereas both a low bone formation rate and a marked increase in osteoclast surface were observed in female βIVSII-654mice. In conclusion, osteopenia and trabecular microstructural defects were present in both male and female βIVSII-654knockin thalassemic mice, but the severity, disease progression, and cellular mechanism differed between the sexes.

scholarly journals Increased Marrow Adiposity in Premenopausal Women with Idiopathic Osteoporosis

2012 ◽  
Vol 97 (8) ◽  
pp. 2782-2791 ◽  
Author(s):  
Adi Cohen ◽  
David W. Dempster ◽  
Emily M. Stein ◽  
Thomas L. Nickolas ◽  
Hua Zhou ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Mass ◽  
Formation Rate ◽  
Premenopausal Women ◽  
Micro Computed Tomography ◽  
Mineral Density ◽  
Marrow Fat ◽  
Bone Formation Rate ◽  
Idiopathic Osteoporosis ◽  
Marrow Adiposity

Abstract Context: We have previously reported that premenopausal women with idiopathic osteoporosis based on fractures (IOP) or idiopathic low bone mineral density (ILBMD) exhibit markedly reduced bone mass, profoundly abnormal trabecular microstructure, and significant deficits in trabecular bone stiffness. Bone remodeling was heterogeneous. Those with low bone turnover had evidence of osteoblast dysfunction and the most marked deficits in microstructure and stiffness. Objective: Because osteoblasts and marrow adipocytes derive from a common mesenchymal precursor and excess marrow fat has been implicated in the pathogenesis of bone fragility in anorexia nervosa, glucocorticoid excess, and thiazolidinedione exposure, we hypothesized that marrow adiposity would be higher in affected women and inversely related to bone mass, microarchitecture, bone formation rate, and osteoblast number. Design: We analyzed tetracycline-labeled transiliac biopsy specimens in 64 premenopausal women with IOP or ILBMD and 40 controls by three-dimensional micro-computed tomography and two-dimensional quantitative histomorphometry to assess marrow adipocyte number, perimeter, and area. Results: IOP and ILBMD subjects did not differ with regard to any adipocyte parameter, and thus results were combined. Subjects had substantially higher adipocyte number (by 22%), size (by 24%), and volume (by 26%) than controls (P &lt; 0.0001 for all). Results remained significant after adjusting for age, body mass index, and bone volume. Controls demonstrated expected direct associations between marrow adiposity and age and inverse relationships between marrow adiposity and bone formation, volume, and microstructure measures. No such relationships were observed in the subjects. Conclusions: Higher marrow adiposity and the absence of expected relationships between marrow adiposity and bone microstructure and remodeling in women with IOP or ILBMD suggest that the relationships between fat and bone are abnormal; excess marrow fat may not arise from a switch from the osteoblast to the adipocyte lineage in this disorder. Whether excess marrow fat contributes to the pathogenesis of this disorder remains unclear.

scholarly journals BK ablation attenuates osteoblast bone formation via integrin pathway

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Yinhang Wang ◽  
Qiang Guo ◽  
Hongya Hei ◽  
Jie Tao ◽  
Yi Zhou ◽  
...  
Keyword(s):  
Bone Formation ◽  
Lumbar Vertebrae ◽  
Mineral Density ◽  
Α Subunit ◽  
Osteoblast Activity ◽  
Marrow Mesenchymal Stem Cells ◽  
Calcium Activated Potassium Channels ◽  
Potential Strategy

Abstract Impaired bone formation is one of the major causes of low bone mass and skeletal fragility that occurs in osteoporosis. However, the mechanisms underlying the defects in bone formation are not well understood. Here, we report that big conductance calcium-activated potassium channels (BKs) are required for bone formation and osteoblast function both in vivo and in vitro. By 15 weeks of age, BK knockout (BKO) mice exhibited a decline in bone mineral density and trabecular bone volume of the tibiae and lumbar vertebrae, which were associated with impaired bone formation and osteoblast activity. Mechanistically, BK ablation in bone and bone marrow mesenchymal stem cells (BMSCs) of BKO mice inhibited integrin signaling. Furthermore, the binding of α subunit of BK with integrin β1 protein in osteoblasts was confirmed, and FAK-ERK1/2 signaling was proved to be involved by genetic modification of KCNMA1 (which encodes the α subunit of BK) in ROS17/2.8 osteoblast cells. These findings indicated that BK regulates bone formation by promoting osteoblast differentiation via integrin pathway, which provided novel insight into ion transporter crosstalk with the extracellular matrix in osteoblast regulation and revealed a new potential strategy for intervention in correcting bone formation defects.

scholarly journals DSS-induced colitis produces inflammation-induced bone loss while irisin treatment mitigates the inflammatory state in both gut and bone

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Corinne E. Metzger ◽  
S. Anand Narayanan ◽  
Jon P. Elizondo ◽  
Anne Michal Carter ◽  
David C. Zawieja ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Therapeutic Potential ◽  
Negative Impact ◽  
Formation Rate ◽  
Inflammatory Factors ◽  
Sprague Dawley ◽  
Mineral Density ◽  
Bone Formation Rate ◽  
Gut Inflammation

Abstract Chronic pediatric inflammatory bowel disease (IBD) leads to lack of bone accrual, bone loss, and increased fractures. Presently there is no cure, and many IBD treatments incur negative side effects. We previously discovered treatment with exogenous irisin resolved inflammatory changes in the colon, gut lymphatics, and bone in a mild IBD rodent model. Here we assess irisin treatment in severe IBD induced via dextran sodium sulfate (DSS). Male Sprague Dawley rats (2-mo-old) were untreated (Con) or given 2% DSS in drinking water. In week two, half of each group (Con + Ir and DSS + Ir) received injections of recombinant irisin (i.p., 2x/wk). After 4 weeks, gut inflammation was associated with declines in bone mineral density and cancellous bone volume. Furthermore, elevated osteocyte TNF-α, interleukin-6, RANKL, OPG, and sclerostin corresponded with higher osteoclast surfaces and lower bone formation rate in DSS animals as well as lower ultimate load. While irisin treatment improved colon inflammation, there were no improvements in bone density or bone mechanical properties; however, irisin elevated bone formation rate, decreased osteoclast surfaces, and reduced osteocyte pro-inflammatory factors. These data highlight the negative impact of chronic gut inflammation on bone as well as the therapeutic potential of irisin as an anti-inflammatory treatment.

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