Abiraterone acetate and enzalutamide both improve outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Optimal sequencing for these agents and whether cross-resistance ...occurs is unknown.
Multicentre review of patients with mCRPC treated with abiraterone acetate and prednisone after progressing on enzalutamide. Primary objective was to determine abiraterone acetate response.
Thirty patients identified from four North American centres. At abiraterone initiation, median age was 70 years (56–84 years); 70% had ECOG performance status of 0–1; all had prior docetaxel. Median prior enzalutamide treatment duration was 41 weeks (6–95 weeks), with 70% (21 of 30) having a ≥30% prostate-specific antigen (PSA) decline. Median abiraterone acetate treatment duration was 13 weeks (1–52). No objective radiographic responses were observed. Median abiraterone time to progression (PSA, objective or symptomatic) was 15.4 weeks 95% confidence interval (CI) 10.7–20.2. Median overall survival was 50.1 weeks (95% CI 28.3–72.0). Three patients had a ≥30% PSA decline with abiraterone. Two of these patients had PSA progression as best response with prior enzalutamide.
In this study of patients progressing after enzalutamide, treatment with abiraterone was associated with a modest response rate and brief duration of effect. Primary progression on enzalutamide may not preclude a response to abiraterone.
Osteocytes, which represent up to 95% of adult skeletal cells, are deeply embedded in bone. These cells exhibit important interactive abilities with other bone cells such as osteoblasts and ...osteoclasts to control skeletal formation and resorption. Beyond this local role, osteocytes can also influence the function of distant organs due to the presence of their sophisticated lacunocanalicular system, which connects osteocyte dendrites directly to the vasculature. Through these networks, osteocytes sense changes in circulating metabolites and respond by producing endocrine factors to control homeostasis. One critical function of osteocytes is to respond to increased blood phosphate and 1,25(OH)
vitamin D (1,25D) by producing fibroblast growth factor-23 (FGF23). FGF23 acts on the kidneys through partner fibroblast growth factor receptors (FGFRs) and the co-receptor Klotho to promote phosphaturia
a downregulation of phosphate transporters, as well as the control of vitamin D metabolizing enzymes to reduce blood 1,25D. In the first part of this review, we will explore the signals involved in the positive and negative regulation of FGF23 in osteocytes. In the second portion, we will bridge bone responses with the review of current knowledge on FGF23 endocrine functions in the kidneys.
During aging, there is a normal and mild loss in kidney function that leads to abnormalities of the kidney-bone metabolic axis. In the setting of increased phosphorus intake, hyperphosphatemia can ...occur despite increased concentrations of the phosphaturic hormone FGF23. This is likely from decreased expression of the FGF23 co-receptor Klotho (KL) with age; however, the roles of age and sex in the homeostatic responses to mild phosphate challenges remain unclear.
Male and female 16-week and 78-week mice were placed on either normal grain-based chow or casein (higher bioavailable phosphate) diets for 8 weeks. Gene expression, serum biochemistries, micro-computed tomography, and skeletal mechanics were used to assess the impact of mild phosphate challenge on multiple organ systems. Cell culture of differentiated osteoblast/osteocytes was used to test mechanisms driving key outcomes.
Aging female mice responded to phosphate challenge by significantly elevating serum intact FGF23 (iFGF23) versus control diet; males did not show this response. Male mice, regardless of age, exhibited higher kidney KL mRNA with similar phosphate levels across both sexes. However, males and females had similar blood phosphate, calcium, and creatinine levels irrespective of age, suggesting that female mice upregulated FGF23 to maintain blood phosphorus, and compromised renal function could not explain the increased serum iFGF23. The 17β-estradiol levels were not different between groups, and in vivo bone steroid receptor (estrogen receptor 1 Esr1, estrogen receptor 2 Esr2, androgen receptor Ar) expression was not different by age, sex, or diet. Trabecular bone volume was higher in males but decreased with both age and phosphate challenge in both sexes. Cortical porosity increased with age in males but not females. In vitro studies demonstrated that 17β-estradiol treatment upregulated FGF23 and Esr2 mRNAs in a dose-dependent manner.
Our study demonstrates that aging female mice upregulate FGF23 to a greater degree during a mild phosphate challenge to maintain blood phosphorus versus young female and young/old male mice, potentially due to direct estradiol effects on osteocytes. Thus, the control of phosphate intake during aging could have modifiable outcomes for FGF23-related phenotypes.
WISP1/CCN4 (hereafter referred to as WISP1), a member of the CCN family, is found in mineralized tissues and is produced by osteoblasts and their precursors. In this study, Wisp1-deficient (Wisp1−/−) ...mice were generated. Using dual-energy x-ray absorptiometry, we showed that by 3 months, the total bone mineral density of Wisp1−/− mice was significantly lower than that of WT mice. Further investigation by micro-computed tomography showed that female Wisp1−/− mice had decreased trabecular bone volume/total volume and that both male and female Wisp1−/− mice had decreased cortical bone thickness accompanied by diminished biomechanical strength. The molecular basis for decreased bone mass in Wisp1−/− mice arises from reduced bone formation likely caused by osteogenic progenitors that differentiate poorly compared with WT cells. Osteoclast precursors from Wisp1−/− mice developed more tartrate-resistant acid phosphatase-positive cells in vitro and in transplants, suggesting that WISP1 is also a negative regulator of osteoclast differentiation. When bone turnover (formation and resorption) was induced by ovariectomy, Wisp1−/− mice had lower bone mineral density compared WT mice, confirming the potential for multiple roles for WISP1 in controlling bone homeostasis. Wisp1−/− bone marrow stromal cells had reduced expression of β-catenin and its target genes, potentially caused by WISP1 inhibition of SOST binding to LRP6. Taken together, our data suggest that the decreased bone mass found in Wisp1−/− mice could potentially be caused by an insufficiency in the osteodifferentiation capacity of bone marrow stromal cells arising from diminished Wnt signaling, ultimately leading to altered bone turnover and weaker biomechanically compromised bones.
Background: WISP1 is expressed in bone, but its roles in osteogenesis are unclear.
Results: WISP1 regulates bone mineral content, cortical and trabecular bone thickness, and bone strength during aging by modulating osteoblast and osteoclast function and Wnt signaling.
Conclusion: WISP1 controls bone integrity by regulating bone turnover.
Significance: WISP1 is a novel target for modulating bone turnover and improving bone strength.
Iron‐deficiency anemia is a potent stimulator of the phosphaturic hormone Fibroblast growth factor‐23 (FGF23). Anemia, elevated FGF23, and elevated serum phosphate are significant mortality risk ...factors for patients with chronic kidney disease (CKD). However, the contribution of anemia to overall circulating FGF23 levels in CKD is not understood. Our goal was to investigate the normalization of iron handling in a CKD model using the erythropoiesis stimulating agents (ESAs) Erythropoietin (EPO) and the hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHDi) FG‐4592, on the production of, and outcomes associated with, changes in bioactive, intact FGF23 (“iFGF23”). Our hypothesis was that rescuing the prevailing anemia in a model of CKD would reduce circulating FGF23. Wild‐type mice were fed an adenine‐containing diet to induce CKD, then injected with EPO or FG‐4592. The mice with CKD were anemic, and EPO improved red blood cell indices, whereas FG‐4592 increased serum EPO and bone marrow erythroferrone (Erfe), and decreased liver ferritin, bone morphogenic protein‐6 (Bmp‐6), and hepcidin mRNAs. In the mice with CKD, iFGF23 was markedly elevated in control mice but was attenuated by >70% after delivery of either ESA, with no changes in serum phosphate. ESA treatment also reduced renal fibrosis markers, as well as increased Cyp27b1 and reduced Cyp24a1 mRNA expression. Thus, improvement of iron utilization in a CKD model using EPO and a HIF‐PHDi significantly reduced iFGF23, demonstrating that anemia is a primary driver of FGF23, and that management of iron utilization in patients with CKD may translate to modifiable outcomes in mineral metabolism.
Iron‐deficiency anemia is a potent stimulator of the phosphaturic hormone FGF23, and anemia, elevated FGF23, and serum phosphate are all significant risk factors for chronic kidney disease (CKD) patient death; however, the contribution of anemia to circulating FGF23 in CKD is not understood. We found that a CKD mouse model treated with EPO or a HIF‐PHDi to restore proper iron utilization had a 70% reduction of circulating iFGF23, normalization of vitamin D metabolic enzymes, and no exacerbation of hyperphosphatemia. In summary, our work demonstrated that the major portion of elevated iFGF23 in CKD is likely due to the associated anemia/iron deficiency, is therapeutically responsive to the control of iron utilization, and may thus provide modifiable patient benefit for mineral handling during CKD.
Mesenchymal progenitors differentiate into several tissues including bone, cartilage, and adipose. Targeting these cells in vivo is challenging, making mesenchymal progenitor cell lines valuable ...tools to study tissue development. Mesenchymal stem cells (MSCs) can be isolated from humans and animals; however, obtaining homogenous, responsive cells in a reproducible fashion is challenging. As such, we developed two mesenchymal progenitor cell (MPC) lines, MPC1 and MPC2, generated from bone marrow of male C57BL/6 mice. These cells were immortalized using the temperature sensitive large T-antigen, allowing for thermal control of proliferation and differentiation. Both MPC1 and MPC2 cells are capable of osteogenic, adipogenic, and chondrogenic differentiation. Under osteogenic conditions, both lines formed mineralized nodules, and stained for alizarin red and alkaline phosphatase, while expressing osteogenic genes including Sost, Fgf23, and Dmp1. Sost and Dmp1 mRNA levels were drastically reduced with addition of parathyroid hormone, thus recapitulating in vivo responses. MPC cells secreted intact (iFGF23) and C-terminal (cFGF23) forms of the endocrine hormone FGF23, which was upregulated by 1,25 dihydroxy vitamin D (1,25D). Both lines also rapidly entered the adipogenic lineage, expressing adipose markers after 4 days in adipogenic media. MPC cells were also capable of chondrogenic differentiation, displaying increased expression of cartilaginous genes including aggrecan, Sox9, and Comp. With the ability to differentiate into multiple mesenchymal lineages and mimic in vivo responses of key regulatory genes/proteins, MPC cells are a valuable model to study factors that regulate mesenchymal lineage allocation as well as the mechanisms that dictate transcription, protein modification, and secretion of these factors.
Due to a lack of spatial-temporal resolution at the single cell level, the etiologies of the bone dysfunction caused by diseases such as normal aging, osteoporosis, and the metabolic bone disease ...associated with chronic kidney disease (CKD) remain largely unknown.
To this end, flow cytometry and scRNAseq were performed on long bone cells from Sost-cre/Ai9
mice, and pure osteolineage transcriptomes were identified, including novel osteocyte-specific gene sets.
Clustering analysis isolated osteoblast precursors that expressed
,
, and
, and a mature osteoblast population defined by
,
, and
. Osteocytes were demarcated by
,
,
,
,
, and
. We validated our
scRNAseq using integrative
promoter occupancy
ATACseq coupled with transcriptomic analyses of a conditional, temporally differentiated MSC cell line. Further, trajectory analyses predicted osteoblast-to-osteocyte transitions
defined pathways associated with a distinct metabolic shift as determined by single-cell flux estimation analysis (scFEA). Using the adenine mouse model of CKD, at a time point prior to major skeletal alterations, we found that gene expression within all stages of the osteolineage was disturbed.
In sum, distinct populations of osteoblasts/osteocytes were defined at the single cell level. Using this roadmap of gene assembly, we demonstrated unrealized molecular defects across multiple bone cell populations in a mouse model of CKD, and our collective results suggest a potentially earlier and more broad bone pathology in this disease than previously recognized.
Introduction The fair lending cases filed by Miami against large mortgage lenders in 2013, in which the city sought to recover lost property tax revenues and increased municipal expenses allegedly ...caused by foreclosures that in turn were caused by the banks' alleged redlining (denying credit on a discriminatory basis) and reverse redlining (targeting predatory loans on a discriminatory basis), have been prominently featured in several previous Annual Surveys.1 They are featured again here because the Eleventh Circuit has issued its long-awaited decision on remand from the U.S. Supreme Court's 2017 decision in Bank of America Corp. v. City of Miami.2 While other municipal fair lending cases were stayed as the court considered petitions for rehearing en banc the remand opinion, which have now been denied,3 the Eleventh Circuit affirmed summary judgment granted in a case brought by the City of Miami Gardens. The Eleventh Circuit's Remand Ruling Almost two years after the Supreme Court ruled in City of Miami that the Eleventh Circuit erred in adopting a foreseeability standard for discrimination claims under the FHA and remanded for further consideration, the Eleventh Circuit's remand opinion was finally handed down in City of Miami v. Wells Fargo & Co 5 As noted in the previous Survey,6 no decision was forthcoming from the Eleventh Circuit, even though the two defendant banks filed motions to remand several months after the Supreme Court's ruling. Wells Fargo's petition argued, among other things, that the court's proximate cause analysis based on a "logical bond" between the violative conduct and the claimed injury did not comport with the Supreme Court's requirement that "direction relation" be alleged,28 and that the "several links" involved in the causal chain took the case outside the Supreme Court's boundaries.29 Bank of America's petition also took issue with the Wells Fargo court's "logical bond" analysis.30 The petitions were denied in August 2019,31 and the many municipal cases that were stayed pending the City of Miami decision on remand32 may now have their stays lifted. ...it found that the district court should have dismissed the case for lack of jurisdiction.
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