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Deterioration of hematopoietic autophagy is linked to osteoporosis.

ABSTRACT: Hematopoietic disorders are known to increase the risk of complications such as osteoporosis. However, a direct link between hematopoietic cellular disorders and osteoporosis has been elusive. Here, we demonstrate that the deterioration of hematopoietic autophagy is coupled with osteoporosis in humans. With a conditional mouse model in which autophagy in the hematopoietic system is disrupted by deletion of the Atg7 gene, we show that incapacitating hematopoietic autophagy causes bone loss and perturbs osteocyte homeostasis. Induction of osteoporosis, either by ovariectomy, which blocks estrogen secretion, or by injection of ferric ammonium citrate to induce iron overload, causes dysfunction in the hematopoietic stem and progenitor cells (HSPCs) similar to that found in autophagy-defective mice. Transcriptomic analysis of HSPCs suggests promotion of iron activity and inhibition of osteocyte differentiation and calcium metabolism by hematopoietic autophagy defect, while proteomic profiling of bone tissue proteins indicates disturbance of the extracellular matrix pathway that includes collagen family members. Finally, screening for expression of selected genes and an immunohistological assay identifies severe impairments in H vessels in the bone tissue, which results in disconnection of osteocytes from hematopoietic cells in the autophagy-defective mice. We therefore propose that hematopoietic autophagy is required for the integrity of H vessels that bridge blood and bone cells and that its deterioration leads to osteoporosis.

SUBMITTER: Yuan Y

PROVIDER: S-EPMC7253060 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Deterioration of hematopoietic autophagy is linked to osteoporosis.

Yuan Ye Y Fang Yixuan Y Zhu Lingjiang L Gu Yue Y Li Lei L Qian Jiawei J Zhao Ruijin R Zhang Peng P Li Jian J Zhang Hui H Yuan Na N Zhang Suping S Ma Quanhong Q Wang Jianrong J Xu Youjia Y

Aging cell 20200325 5

Hematopoietic disorders are known to increase the risk of complications such as osteoporosis. However, a direct link between hematopoietic cellular disorders and osteoporosis has been elusive. Here, we demonstrate that the deterioration of hematopoietic autophagy is coupled with osteoporosis in humans. With a conditional mouse model in which autophagy in the hematopoietic system is disrupted by deletion of the Atg7 gene, we show that incapacitating hematopoietic autophagy causes bone loss and pe ...[more]

PMID: 32212304

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Project description:Introduction: Hospitalized pediatric hematology-oncology and post-hematopoietic cell transplant (HCT) patients have frequent deterioration requiring Pediatric Intensive Care Unit (PICU) care. Critical deterioration (CD), defined as unplanned PICU transfer requiring life-sustaining interventions within 12 h, is a pragmatic metric to evaluate emergency response systems (ERS) in pediatrics, however, it has not been investigated in these patients. The goal of this study was to evaluate if CD is an appropriate metric to assess effectiveness of ERS in pediatric hematology-oncology and post-HCT patients and if it is preceded by an actionable period of vital sign changes. Methods: A retrospective review of all unplanned PICU transfers and floor cardiopulmonary arrests in a dedicated pediatric hematology-oncology hospital between August 2014 and July 2016. Vital signs and physical exam findings 48 h prior to events were converted to Pediatric Early Warning System-Like Scores (PEWS-LS) using cardiovascular, respiratory, and neurologic criteria. Results: There were 220 deterioration events, with 107 (48.6%) meeting criteria for CD, representing a rate of 2.98 per 1,000-inpatient-days. Using the first event per hospitalization (n = 184), patients with CD had higher mortality (17.4 vs. 7.6%, p = 0.045), fewer median ICU-free-days (21 vs. 24, p = 0.011), ventilator-free-days (25 vs. 28, p < 0.001), and vasoactive-free-days (27 vs. 28, p < 0.001). Using vital sign data 48 h prior to deterioration events, those with CD had higher PEWS-LS on PICU admission (p < 0.001), spent more time with elevated PEWS-LS prior to PICU transfer (p = 0.008 to 0.023) and had a longer time from first abnormal PEWS-LS (p = 0.007 to 0.043). Significant difference between the two groups was observed as early as 4 h prior to the event (p = 0.047). Conclusion: Hospitalized pediatric hematology-oncology and post-HCT patients have frequent deterioration resulting in a high mortality. In these patients, CD is over 13 times more common than floor cardiopulmonary arrests and associated with higher mortality and fewer event-free days, making it a useful metric in these patients. CD is preceded by a long duration of abnormal vital signs, making it potentially preventable through earlier recognition.

Project description:BACKGROUND:Skeletal damage is a challenge for laying hens because the physiological adaptations required for egg laying make them susceptible to osteoporosis. Previously, we showed that genetic factors explain 40% of the variation in end of lay bone quality and we detected a quantitative trait locus (QTL) of large effect on chicken chromosome 1. The aim of this study was to combine data from the commercial founder White Leghorn population and the F2 mapping population to fine-map this QTL and understand its function in terms of gene expression and physiology. RESULTS:Several single nucleotide polymorphisms on chromosome 1 between 104 and 110 Mb (galGal6) had highly significant associations with tibial breaking strength. The alternative genotypes of markers of large effect that flanked the region had tibial breaking strengths of 200.4 vs. 218.1 Newton (P?<?0.002) and, in a subsequent founder generation, the higher breaking strength genotype was again associated with higher breaking strength. In a subsequent generation, cortical bone density and volume were increased in individuals with the better bone genotype but with significantly reduced medullary bone quality. The effects on cortical bone density were confirmed in a further generation and was accompanied by increased mineral maturity of the cortical bone as measured by infrared spectrometry and there was evidence of better collagen cross-linking in the cortical bone. Comparing the transcriptome of the tibia from individuals with good or poor bone quality genotypes indicated four differentially-expressed genes at the locus, one gene, cystathionine beta synthase (CBS), having a nine-fold higher expression in the genotype for low bone quality. The mechanism was cis-acting and although there was an amino-acid difference in the CBS protein between the genotypes, there was no difference in the activity of the enzyme. Plasma homocysteine concentration, the substrate of CBS, was higher in the poor bone quality genotype. CONCLUSIONS:Validated markers that predict bone strength have been defined for selective breeding and a gene was identified that may suggest alternative ways to improve bone health in addition to genetic selection. The identification of how genetic variants affect different aspects of bone turnover shows potential for translational medicine.

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Deterioration of hematopoietic autophagy is linked to osteoporosis.

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Deterioration of hematopoietic autophagy is linked to osteoporosis.

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