Bone最新文献

{"title":"microRNA-324 mediates bone homeostasis and the regulation of osteoblast and osteoclast differentiation and activity","authors":"Dan J. Hayman ,&nbsp;Francesca M. Johnson de Sousa Brito ,&nbsp;Hua Lin ,&nbsp;Amanda Prior ,&nbsp;Gemma Charlesworth ,&nbsp;Yao Hao ,&nbsp;Rachel D. Pearson ,&nbsp;Jamie Soul ,&nbsp;Ian M. Clark ,&nbsp;Katarzyna A. Piróg ,&nbsp;Matt J. Barter ,&nbsp;Rob J. van't Hof ,&nbsp;David A. Young","doi":"10.1016/j.bone.2024.117273","DOIUrl":"10.1016/j.bone.2024.117273","url":null,"abstract":"<div><div>MicroRNAs (miRNAs) modulate the expression of other RNA molecules. One miRNA can target many transcripts, allowing each miRNA to play key roles in many biological pathways. Defects in bone homeostasis result in common age-related diseases including osteoporosis. Serum levels of miR-324-3p positively correlate with several features of bone maintenance. In contrast here, using <em>in vivo</em> micro-computed tomography and histology, global miR-324-null mice demonstrated increased bone mineral density and both trabecular and cortical thickness, with effect magnitudes increasing with age. The bone marrow of miR-324-null mice had reduced lipid content while TRAP staining revealed a decrease in osteoclasts, with histomorphometry demonstrating an increased rate of bone formation. <em>Ex vivo</em> assays showed that the high bone mass phenotype of miR-324-null mice resulted from both increased osteoblast activity and decreased osteoclastogenesis. RNA-seq analysis of osteoblasts, osteoclasts and bone marrow macrophages and target validation assays identified that the osteoclast fusion regulator <em>Pin1</em> and the master osteogenic regulator <em>Runx2</em> were targets of miR-324-5p in osteoclast lineage cells and osteoblasts, respectively. Indeed, <em>in vitro</em> Runx2 overexpression recapitulated the increased osteogenesis and decreased adipogenesis phenotype observed <em>in vivo</em> by the loss of miR-324. Overall, these data demonstrate the importance of miR-324 in bone homeostasis by regulating aspects of both bone formation and remodelling. Elucidation of pathways regulated by miR-324 offer promise for the treatment of bone diseases such as osteoporosis.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"190 ","pages":"Article 117273"},"PeriodicalIF":3.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictors of lumbar spine trabecular bone score in women with postsurgical hypoparathyroidism","authors":"Ana Rachel Teixeira Batista Carvalho ,&nbsp;Daniel Humberto Dias Freire ,&nbsp;Alaor Barra Sobrinho ,&nbsp;Angélica Amorim Amato","doi":"10.1016/j.bone.2024.117274","DOIUrl":"10.1016/j.bone.2024.117274","url":null,"abstract":"<div><div>Hypoparathyroidism is a rare disease that markedly reduces bone remodeling, leading to increased bone mineral density and changes in bone microarchitecture. However, it is currently unclear how these changes affect fracture risk. In this study, we investigated bone mass by dual-energy x-ray absorptiometry, the occurrence of morphometric vertebral fractures, and bone microarchitecture by assessing trabecular bone score in women with postsurgical hypoparathyroidism. We included 67 women with hypoparathyroidism aged 52.9 ± 12.3 years and 63 age- and body mass index-matched controls, which were assessed for femoral and lumbar spine bone mineral density, trabecular bone score, and vertebral fractures by dual-energy x-ray absorptiometry. Women with hypoparathyroidism had significantly higher bone mineral density at the lumbar spine, femoral neck, and total hip compared with controls despite similar trabecular bone score values. Vertebral fracture assessment indicated that two women with hypoparathyroidism presented vertebral fractures, both aged over 65 years. Conversely, no vertebral fractures were detected in control women. In a multivariate linear regression model, we found that older age, diabetes, and lower lumbar spine mineral density were significant predictors of lower trabecular bone score values. Our findings indicate that vertebral fractures are not common among women with postsurgical hypoparathyroidism aged under 65 years. Moreover, trabecular bone score values were similar in women with hypoparathyroidism and age-matched controls and were associated with traditional risk factors for fractures, such as older age, type 2 diabetes, and lower spine bone mineral density.</div></div><div><h3>Lay summary</h3><div>Chronic parathyroid hormone deficiency decreases bone turnover and modifies skeletal properties, although the impact of these changes on fracture risk remains unclear. We studied 67 women with postsurgical hypoparathyroidism and 63 age and body mass index-matched healthy controls and found that bone mineral density is increased in women with hypoparathyroidism despite similar trabecular bone score values and a low occurrence of morphometric vertebral fractures. This suggests that the low bone turnover in hypoparathyroidism increases bone mass, but this is not accompanied by improved bone microarchitecture, indicating that trabecular bone score may be a valuable tool to complement the assessment of skeletal health and the risk of fractures in this condition.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"190 ","pages":"Article 117274"},"PeriodicalIF":3.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142395937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of dopaminergic neuron degeneration on osteocyte apoptosis and osteogenic markers in 6-OHDA male rat model of Parkinson's disease","authors":"Latifa Knani ,&nbsp;Massimo Venditti ,&nbsp;Hajer Rouis ,&nbsp;Sergio Minucci ,&nbsp;Imed Messaoudi","doi":"10.1016/j.bone.2024.117271","DOIUrl":"10.1016/j.bone.2024.117271","url":null,"abstract":"<div><div>Parkinson's disease (PD) and osteoporosis are prevalent chronic conditions that impact a significant proportion of the aging population. Observational and longitudinal studies consistently demonstrate that individuals with PD face an elevated risk of osteoporosis and reduced bone mineral density compared to control groups. However, there is currently no experimental evidence demonstrating the impact of dopaminergic neuron degeneration on bone metabolism. In the present study, we used a male rat model of PD induced by unilateral injection of 6-hydroxydopamine (6-OHDA) in the left medial forebrain bundle (MFB) to evaluate the effect of dopaminergic neuron lesion on certain parameters of bone metabolism. To confirm the dopaminergic neuron lesion, cylinder and Rotarod tests were applied to rats injected with 6-OHDA or vehicle. Osteocyte density and viability were determined through histology and TUNEL assay. Western Blot and immunohistochemistry analysis were performed to investigate whether dopaminergic degeneration influences the expression of some apoptotic markers (Caspase 3 and Cytochrome C) and some osteogenic markers (ALP, OCN, and RUNX2). Our findings show that the dopaminergic lesion resulting from the injection of 6-OHDA was successfully confirmed through behavioral tests. Furthermore, the degeneration of dopaminergic neurons induced by 6-OHDA leads to apoptosis of osteocytes associated with a significant reduction in the tissue expression of the studied osteogenic markers. Thus, our study provides evidence that 6-OHDA-induced degeneration of dopaminergic neurons leads to osteocyte apoptosis, which may contribute to the development of some signs of osteoporosis.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"190 ","pages":"Article 117271"},"PeriodicalIF":3.5,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aerobic exercise training-induced bone and vascular adaptations in mice lacking adiponectin","authors":"Hyerim Park ,&nbsp;Samuel P. Trupiano ,&nbsp;Steven L. Medarev ,&nbsp;Payal Ghosh ,&nbsp;Jacob T. Caldwell ,&nbsp;Joshua F. Yarrow ,&nbsp;Judy M. Muller-Delp","doi":"10.1016/j.bone.2024.117272","DOIUrl":"10.1016/j.bone.2024.117272","url":null,"abstract":"<div><div>Adiponectin regulates lipid and glucose metabolism, and insulin sensitivity in various target organs; however, the effects of adiponectin on bone health remain controversial. Exercise training can enhance bone density, bone microarchitecture, and blood flow. This study aimed to elucidate the role of adiponectin in adaptations of bone microarchitecture and bone vasculature in response to aerobic exercise training.</div><div>Adult male C57BL/6 wild-type (WT) and homozygous adiponectin knockout (AdipoKO) mice were either treadmill exercise trained or remained sedentary for 8–10 weeks. The trabecular structures of the distal femoral metaphysis, a weight-bearing bone, and the mandible, a non-weight-bearing bone, were examined using microcomputed tomography. The femoral principal nutrient arteries were isolated to assess vasoreactivity (vasodilation and vasoconstriction) and structural remodeling.</div><div>At the femoral metaphysis, impaired trabecular bone structures, including reduced connectivity density and increased trabecular spacing, were observed in AdipoKO mice compared to WT mice. In addition, nitric oxide-mediated, endothelium-dependent vasodilation was substantially reduced, and wall-to-lumen ratio was significantly increased in the femoral principal nutrient artery of AdipoKO mice. Interestingly, although exercise training-induced enhancements in trabecular connectivity density were observed at the femoral metaphysis of both WT and AdipoKO, increased vasoconstrictor responses were only observed in the femoral principal nutrient artery of WT mice, not in the AdipoKO mice. In mandibular trabecular bone, exercise training increased trabecular bone volume fraction (BV/TV, %) and intersection surface in the mandible of both WT and AdipoKO mice.</div><div>These findings indicate that adiponectin is crucial for maintaining normal bone microarchitecture and vasculature. Although the absence of adiponectin compromises bone vascular adaptation to exercise training in mice, some exercise training-induced alterations in bone microarchitecture occurred in the absence of adiponectin, suggesting contribution of compensatory mechanisms during exercise training.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"190 ","pages":"Article 117272"},"PeriodicalIF":3.5,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142382754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A systematic review of mesenchymal stem cell secretome: Functional annotations, gene clusters and proteomics analyses for bone formation","authors":"Dia Advani ,&nbsp;Nouran Farid ,&nbsp;Muhammad Hamza Tariq ,&nbsp;Nupur Kohli","doi":"10.1016/j.bone.2024.117269","DOIUrl":"10.1016/j.bone.2024.117269","url":null,"abstract":"<div><div>The regenerative capacity of mesenchymal stem cells (MSCs) is now attributed to their ability to release paracrine factors into the extracellular matrix that boost tissue regeneration, reduce inflammation and encourage healing. Understanding the MSC secretome is crucial for shifting the prototypic conventional cell-based therapies to cell-free regenerative treatments. This systematic review aimed to analyse the functional annotations of the secretome of human adult adipose tissue and bone marrow MSCs and unveil the gene clusters responsible for bone formation. Bioinformatics tools were used to identify the biological processes, molecular functions, hallmarks and KEGG pathways of adipose and bone marrow MSC secretome proteins. We found a substantial overlap in the functional annotations and protein compositions of both adipose and bone marrow MSC secretome indicating that MSC source may be noninfluencial with regards to tissue regeneration. Additionally, a novel network pharmacology-based analysis of the secreted proteins revealed that the commonly secreted proteins within a single source interact with multiple drugable targets of bone diseases and regulate various KEGG pathway. This study unravels the secretome profile of human adult adipose and bone marrow MSCs based on the current literature and provides valuable insights into the therapeutic use of the MSC secretome for cell-free therapies.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"190 ","pages":"Article 117269"},"PeriodicalIF":3.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone loss after bariatric surgery is observed mainly in the hip trabecular compartment and after hypoabsorptive techniques","authors":"Carmen Gómez-Vaquero ,&nbsp;Mirella López Picazo ,&nbsp;Ludovic Humbert ,&nbsp;Laura Hernández-Montoliu ,&nbsp;Olga Jermakova ,&nbsp;Lydia Huanuco ,&nbsp;Mishell Silva ,&nbsp;Javier Osorio ,&nbsp;Claudio Lazzara ,&nbsp;Lucía Sobrino ,&nbsp;Fernando Guerrero-Pérez ,&nbsp;Nuria Vilarrasa","doi":"10.1016/j.bone.2024.117270","DOIUrl":"10.1016/j.bone.2024.117270","url":null,"abstract":"<div><div>We evaluated the impact of bariatric surgery on bone mineral density (BMD) and microarchitecture over one year using dual-energy X-ray absorptiometry (DXA), the trabecular bone score (TBS), and 3D-DXA to assess changes after different surgical techniques. This prospective, single-center study of 153 patients with severe obesity contrasts the effects on bone health of sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and duodenal switch/single anastomosis duodeno-ileostomy with sleeve gastrectomy (DS/SADIS). To our knowledge, this is the first study to evaluate patients undergoing DS/SADIS and to incorporate 3D-DXA analysis in the assessment of bone loss.</div><div>Patients were 81 % female with a mean age of 50 ± 9 years. Fifty-four per cent underwent SG; 16 %, RYGB; and 30 %, DS/SADIS. Our findings revealed a significant decrease in areal BMD at the LS (−3.49 ± 5.44 %), FN (−5.24 ± 5.86 %), and TH (−8.06 ± 5.14 %) one year after bariatric surgery. Bone microarchitecture at the LS assessed by TBS was degraded in 30 % of patients. Proximal femur 3D-DXA analysis showed that surgery-induced bone loss predominantly affects the trabecular compartment (Trabecular volumetric (v) BMD: −8.00 ± 6.57 %) rather than the cortical compartment (Cortical vBMD: −1.37 ± 2.79 %).</div><div>These results suggest hypoabsorptive and mixed techniques (DS/SADIS and RYGB) were associated with greater BMD loss and deterioration of microarchitecture than restrictive techniques (SG).</div><div>The primary determinants of bone density and impairment of microarchitecture were the extent of weight loss and the type of surgical procedure. Despite overall bone loss, <em>Z</em>-score assessments indicated that post-surgical bone status remained within or above the average ranges compared to a healthy population, except for TH following DS/SADIS.</div><div>In conclusion, our research shows differences in the impact of bariatric surgery techniques on bone density and microarchitecture, emphasizing the need for careful postoperative monitoring of bone health, particularly in patients undergoing hypoabsorptive and mixed procedures.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"190 ","pages":"Article 117270"},"PeriodicalIF":3.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meeting report from the 3rd ISCBH-ERN BOND Achondroplasia Workshop on Long Bone Pathology in Children with Achondroplasia, Salzburg, Austria 22nd June 2024","authors":"Moira S. Cheung ,&nbsp;Inês Alves ,&nbsp;Patricia Carl-Innig ,&nbsp;Deborah Eastwood ,&nbsp;Mohamad Maghnie ,&nbsp;Amaka Offiah ,&nbsp;Dror Paley ,&nbsp;Simone Riganti ,&nbsp;Ravi Savarirayan ,&nbsp;Marco Sessa ,&nbsp;Bjoern Vogt ,&nbsp;Klaus Mohnike","doi":"10.1016/j.bone.2024.117268","DOIUrl":"10.1016/j.bone.2024.117268","url":null,"abstract":"<div><div>A pre-meeting workshop on Long Bone Pathology in Children with Achondroplasia was held in Salzburg, Austria at the 11th International Conference on Children's Bone Health (ICCBH) 22–25 June 2024. There remains poor understanding and awareness amongst physicians managing achondroplasia of the underlying pathophysiology, radiology, natural history and orthopaedic procedures available for long bone deformities and restrictions. The structure of the workshop consisted of presentation of the results of a multinational patient survey on views of leg lengthening in achondroplasia, lectures, a debate and an interactive round table discussion. In total 150 attendees from 71 different cities and 31 countries were in attendance.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"190 ","pages":"Article 117268"},"PeriodicalIF":3.5,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The association between fracture and short-term adverse health outcomes among children with cerebral palsy","authors":"Daniel G. Whitney ,&nbsp;Noelle S.B. Whyte ,&nbsp;Michelle S. Caird","doi":"10.1016/j.bone.2024.117267","DOIUrl":"10.1016/j.bone.2024.117267","url":null,"abstract":"<div><h3>Background</h3><div>Children with cerebral palsy (CP) have a high risk of fracture; yet, little is known about their post-fracture health outcomes. A fracture is an unplanned event in contrast to surgeries or procedures where there is a pre-operative period to optimize body composition and health and planned post-operative follow-up care. Fractures may be associated with significant outcomes due to the unplannable nature and reactionary care. The objective of this study was to determine if fractures were associated with an increased rate of short-term adverse health outcomes among children with CP, and if these associations were dependent on age.</div></div><div><h3>Methods</h3><div>This retrospective cohort study used commercial claims from 01/01/2001–12/31/2018. The primary cohort was children 2–18 years old with CP and an incident fracture (CP + Fx). Comparison cohorts were propensity score matched 1:1 to CP + Fx on demographic and health-related indicators: CP without fractures (CPw/oFx); without CP with (w/oCP + Fx) or without (w/oCPw/oFx) a fracture. The incidence rate (IR) and IR ratios (IRR) of 30-day and 31–90-day pneumonia and 90-day emergency department (ED) visit were estimated. Cox regression tested for effect modification by age and sex.</div></div><div><h3>Results</h3><div>The CP + Fx cohort (<em>n</em> = 1670) had higher IRs of 30-day pneumonia (IRR range, 1.53–4.54) and 90-day ED visit (IRR range, 1.45–2.37) (all <em>P</em> &lt; 0.05), and higher IRs of 31–90-day pneumonia but this did not reach statistical significance (IRR, 1.41 to 2.32, all <em>P</em> &gt; 0.05). Notably, there was evidence of effect modification by age. The rate of 30-day pneumonia became more problematic for CP + Fx with older age relative to comparison cohorts and for 90-day ED visit compared to CPw/oFx. The rate of 90-day ED visit for CP + Fx was more problematic at younger ages compared to w/oCP + Fx.</div></div><div><h3>Conclusions</h3><div>Fractures among children with CP were associated with an increased rate of short-term pneumonia and ED visit, which was more problematic with older age.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"189 ","pages":"Article 117267"},"PeriodicalIF":3.5,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phlpp1 alters the murine chondrocyte phospho-proteome during endochondral bone formation","authors":"Samantha R. Weaver ,&nbsp;Eduardo Peralta-Herrera ,&nbsp;Haydee M. Torres ,&nbsp;Erik Jessen ,&nbsp;Elizabeth W. Bradley ,&nbsp;Jennifer J. Westendorf","doi":"10.1016/j.bone.2024.117265","DOIUrl":"10.1016/j.bone.2024.117265","url":null,"abstract":"<div><div>Appendicular skeletal growth and bone mass acquisition are controlled by a variety of growth factors, hormones, and mechanical forces in a dynamic process called endochondral ossification. In long bones, chondrocytes in the growth plate proliferate and undergo hypertrophy to drive bone lengthening and mineralization. Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 and 2 (Phlpp1 and Phlpp2) are serine/threonine protein phosphatases that regulate cell proliferation, survival, and maturation via Akt, PKC, Raf1, S6k, and other intracellular signaling cascades. Germline deletion of Phlpp1 suppresses bone lengthening in growth plate chondrocytes. Here, we demonstrate that Phlpp2 does not regulate endochondral ossification, and we define the molecular differences between Phlpp1 and Phlpp2 in chondrocytes. Phlpp2^−/− mice were phenotypically indistinguishable from their wildtype (WT) littermates, with similar bone length, bone mass, and growth plate dynamics. Deletion of Phlpp2 had moderate effects on the chondrocyte transcriptome and proteome compared to WT cells. By contrast, Phlpp1/2^−/− (double knockout) mice resembled Phlpp1^−/− mice phenotypically and molecularly, as the chondrocyte phospho-proteomes of Phlpp1^−/− and Phlpp1/2^−/− chondrocytes had similarities and were significantly different from WT and Phlpp2^−/− chondrocyte phospho-proteomes. Data integration via multiparametric analysis showed that the transcriptome explained less variation in the data as a result of Phlpp1 or Phlpp2 deletion than proteome or phospho-proteome. Alterations in cell proliferation, collagen fibril organization, and Pdpk1 and Pak1/2 signaling pathways were identified in chondrocytes lacking Phlpp1, while cell cycle processes and Akt1 and Aurka signaling pathways were altered in chondrocytes lacking Phlpp2. These data demonstrate that Phlpp1, and to a lesser extent Phlpp2, regulate multiple and complex signaling cascades across the chondrocyte transcriptome, proteome, and phospho-proteome and that multi-omic data integration can reveal novel putative kinase targets that regulate endochondral ossification.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"189 ","pages":"Article 117265"},"PeriodicalIF":3.5,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lif-deficiency promote systemic Iron metabolism disorders and increases the susceptibility of osteoblasts to ferroptosis","authors":"Yu Zhang ,&nbsp;Yaqi Cong ,&nbsp;Juan Du ,&nbsp;Donghua Guo ,&nbsp;Jing Huang ,&nbsp;Junchen Pan ,&nbsp;Youde Liang ,&nbsp;Jiali Zhang ,&nbsp;Zhou Ye ,&nbsp;Yi Liu ,&nbsp;Yi Zhou","doi":"10.1016/j.bone.2024.117266","DOIUrl":"10.1016/j.bone.2024.117266","url":null,"abstract":"<div><div>Leukemia inhibitory factor (LIF) is a multifunctional cytokine that plays a crucial role in various biological processes. However, LIF involvement in iron metabolism remains almost unexplored. This study aimed to explore the impact of LIF on systemic iron transportation and its potential role in ferroptosis in osteoblasts. We observed that the <em>Lif</em>-deficient (<em>Lif</em>^{<em>−/−</em>}) mice is characterized by a reduction in bone mass and a decrease in bone mineral density compared with wild-type (WT) mice. Energy-dispersive X-ray spectroscopy revealed a marked increase in iron content on the surface of femurs from <em>Lif</em>^{<em>−/−</em>} mice. Meanwhile, iron stores test lower iron levels in the spleens and higher levels in the femurs of <em>Lif</em>^{<em>−/−</em>} mice. Besides, <em>Lif</em>^{<em>−/−</em>} mice display increased levels of serum iron, total iron-binding capacity, unsaturated iron-binding capacity, and transferrin saturation and serum ferritin relative to WT mice. Hepcidin mRNA expression reduction in the liver of <em>Lif</em>^{<em>−/−</em>} mice. It also holds true in the AML-12 hepatocyte cell line after <em>Lif</em>-knockdown. Immunohistochemistry and RT-PCR revealed elevated ferroportin (FPN) in duodenal cells of <em>Lif</em>^{<em>−/−</em>} mice. <em>Lif</em>-deficiency decreases SLC7A11 levels in osteoblasts. In addition, overexpression of LIF downregulates CD71, DCYTB, and DMT1, thereby reducing iron uptake in iron-overloaded cells. Femur immunohistochemistry (IHC) revealed increased ACSL4 and decreased GPX4 and SLC7A11, indicating an increase in ferroptosis of osteoblasts in <em>Lif</em>^{<em>−/−</em>} mice. Whole-transcriptome sequencing showed gene expression changes after <em>Lif</em>-knockdown, exhibiting a negative correlation with genes involved in long-chain fatty acid transport, mitochondrial organization, and the p38 MAPK signaling pathway. These results demonstrate that <em>Lif</em>-deficiency alter systemic iron metabolism and increases the susceptibility of osteoblasts to ferroptosis.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"189 ","pages":"Article 117266"},"PeriodicalIF":3.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142334334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}