Multinucleation resets human macrophages for specialized functions at the expense of their identity DOI Creative Commons
Kourosh Ahmadzadeh, Marie Pereira,

Margot Vanoppen

et al.

EMBO Reports, Journal Year: 2023, Volume and Issue: 24(3)

Published: Jan. 4, 2023

Abstract Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans (LGCs) part of granulomas or foreign‐body (FBGCs) reaction exogenous material. How per se contributes functional specialization mature mononuclear macrophages remains poorly understood humans. Here, we integrate comparative transcriptomics with assays purified human osteoclasts, LGCs FBGCs. Strikingly, all three types MGCs, causes a pronounced downregulation macrophage identity. We show enhanced lysosome‐mediated intracellular iron homeostasis promoting MGC formation. The transition from multinuclear state is accompanied by specific each polykaryon. Enhanced phagocytic mitochondrial function associate FBGCs respectively. Moreover, preferentially express B7‐H3 (CD276) can granuloma‐like clusters vitro , suggesting that their potentiates T activation. These findings demonstrate how cell–cell reset identity an advanced maturation step confers MGC‐specific functionality.

Language: Английский

Isobavachin attenuates osteoclastogenesis and periodontitis-induced bone loss by inhibiting cellular iron accumulation and mitochondrial biogenesis DOI

Ting Li,

Yangge Du, Hantao Yao

et al.

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 224, P. 116202 - 116202

Published: April 12, 2024

Language: Английский

Citations

7
Iron metabolism and ferroptosis in diabetic bone loss: from mechanism to therapy DOI Creative Commons
Jiahao Bao,

Yixuan Yan,

Daihui Zuo

et al.

Frontiers in Nutrition, Journal Year: 2023, Volume and Issue: 10

Published: May 5, 2023

Osteoporosis, one of the most serious and common complications diabetes, has affected quality life a large number people in recent years. Although there are many studies on mechanism diabetic osteoporosis, information is still limited no consensus. Recently, researchers have proven that osteoporosis induced by diabetes mellitus may be connected to an abnormal iron metabolism ferroptosis inside cells under high glucose situations. However, comprehensive reviews reported. Understanding these mechanisms important implications for development treatment osteoporosis. Therefore, this review elaborates changes bones conditions, consequences elevated microenvironment associated cells, impact conditions signaling pathways contribute bone loss presence metabolism. Lastly, we also elucidate discuss therapeutic targets with relevant medications which provides some inspiration its cure.

Language: Английский

Citations

16
Novel Insights into Osteoclast Energy Metabolism DOI Creative Commons
María G. Ledesma-Colunga, Vanessa Passin,

Franziska Lademann

et al.

Current Osteoporosis Reports, Journal Year: 2023, Volume and Issue: 21(6), P. 660 - 669

Published: Oct. 10, 2023

Abstract Purpose of Review Osteoclasts are crucial for the dynamic remodeling bone as they resorb old and damaged bone, making space new bone. Metabolic reprogramming in these cells not only supports phenotypic changes, but also provides necessary energy their highly energy-consuming activity, resorption. In this review, we highlight recent developments our understanding metabolic adaptations that influence osteoclast behavior overall tissue. Recent Findings undergo to meet demands during transition from precursor fully mature bone-resorbing osteoclasts. research has made considerable progress pinpointing checkpoint proteins process. Notably, glucose metabolism, mitochondrial biogenesis, oxidative respiration were identified essential pathways involved differentiation, cytoskeletal organization, resorptive activity. Furthermore, interaction between amino acid lipid metabolism adds complexity These interconnected processes can function diverse fuel sources or have independent regulatory effects, significantly influencing function. Summary Energy osteoclasts involves various substrates energetic requirements throughout maturation stages. This biology may provide valuable insights modulating activity pathogenesis bone-related disorders pave way development innovative therapeutic strategies.

Language: Английский

Citations

16
Carnitine functions as an enhancer of NRF2 to inhibit osteoclastogenesis via regulating macrophage polarization in osteoporosis DOI
Tao Yang, Shijie Liu, Haiwei Ma

et al.

Free Radical Biology and Medicine, Journal Year: 2024, Volume and Issue: 213, P. 174 - 189

Published: Jan. 21, 2024

Language: Английский

Citations

5
Early onset of pathological polyploidization and cellular senescence in hepatocytes lacking RAD51 creates a pro-fibrotic and pro-tumorigenic inflammatory microenvironment DOI Creative Commons

Wenqing Bu,

Xue Sun, Xiaotong Xue

et al.

Hepatology, Journal Year: 2024, Volume and Issue: unknown

Published: March 11, 2024

Background and Aims: RAD51 recombinase (RAD51) is a highly conserved DNA repair protein indispensable for embryonic viability. As result, the role of in liver development function unknown. Our aim was to characterize postnatal development. Approach Results: expressed during regeneration following hepatectomy hepatic injury, also elevated chronic diseases. We generated hepatocyte-specific Rad51 deletion mouse model using Alb -Cre ( -conditional knockout (CKO)) Adeno-associated virus 8-thyroxine-binding globulin-cyclization recombination enzyme evaluate regeneration. The phenotype -CKO mice dependent on CRE dosage, with fl/fl ; +/+ manifesting more severe than +/− mice. hepatocytes results aborted mitosis early onset pathological polyploidization that associated oxidative stress cellular senescence. Remarkable fibrosis occurs spontaneously as 3-month-old While compromised mice, they are tolerant carbon tetrachloride–induced injury resistant diethylnitrosamine/carbon HCC. A inflammatory microenvironment created by senescent appears activate ductular reaction transdifferentiation cholangiocytes hepatocytes. newly derived functional immature proliferate vigorously, acquire increased malignancy, eventually give rise Conclusions: demonstrate novel development, homeostasis, tumorigenesis. represent unique genetic premature senescence, fibrosis, hepatocellular carcinogenesis.

Language: Английский

Citations

4
Molecular and functional mapping of Plekhm1-Rab7 interaction in osteoclasts DOI Creative Commons
Bhaba Krishna Das, Tarun Minocha,

Mikaela D Kunika

et al.

JBMR Plus, Journal Year: 2024, Volume and Issue: 8(5)

Published: March 12, 2024

Abstract Mutations in PLEKHM1 cause osteopetrosis humans and rats. The germline osteoclast conditional deletions of Plekhm1 gene mice lead to defective bone resorption increased trabecular mass without overt abnormalities other organs. As an adaptor protein, pleckstrin homology RUN domain containing M1 (PLEKHM1) interacts with the key lysosome regulator small GTPase RAB7 via its C-terminal RUBICON homologous (RH) domain. In this study, we have conducted a structural-functional study RH interaction osteoclasts vitro. single mutations residues predicted from crystal structure interface failed disrupt Plekhm1-Rab7 binding, trafficking, resorption. compound alanine at Y949-R954 L1011-I1018 regions decreased protein stability Rab7-binding, respectively, thereby attenuated trafficking osteoclasts. contrast, R1060-Q1068 region were dispensable for Rab7-binding function These results indicate that spanning are functionally important offer therapeutic targets blocking treatment osteoporosis metabolic diseases.

Language: Английский

Citations

4
Altered Iron-Mediated Metabolic Homeostasis Governs the Efficacy and Toxicity of Tripterygium Glycosides Tablets Against Rheumatoid Arthritis DOI Creative Commons

Zihe Ding,

Xiaoyue Wang,

Yi Zhang

et al.

Engineering, Journal Year: 2024, Volume and Issue: 39, P. 166 - 179

Published: April 23, 2024

Rheumatoid arthritis (RA), a globally increasing autoimmune disorder, is associated with increased disability rates due to the disruption of iron metabolism. Tripterygium glycoside tablets (TGTs), wilfordii Hook. f. (TwHF)-based therapy, exhibit satisfactory clinical efficacy for RA treatment. However, drug-induced liver injury (DILI) remains critical issue that hinders application TGTs, and molecular mechanisms underlying toxicity TGTs in have not been fully elucidated. To address this problem, we integrated multi-omics data anti-RA DILI chemical target profiling perform systematic network analysis. Subsequently, identified effective toxic targets following experimental validation collagen-induced (CIA) mouse model. Significantly different transcriptome–protein–metabolite profiles distinguishing patients favorable responses from those poor outcomes were identified. Intriguingly, against metabolic homeostasis between bone lipids, respectively. Particularly, signal transducer activator transcription 3 (STAT3)–hepcidin (HAMP)/lipocalin 2 (LCN2)–tartrate-resistant acid phosphatase type 5 (ACP5) STAT3–HAMP–acyl-CoA synthetase long-chain family member 4 (ACSL4)–lysophosphatidylcholine acyltransferase (LPCAT3) axes as key drivers TGTs. play dual roles ameliorating CIA-induced pathology inducing hepatic dysfunction, lipid metabolism, peroxidation. Notably, effectively reversed "iron–bone" disruptions inflamed joint tissues CIA mice by inhibiting STAT3–HAMP/LCN2–ACP5 axis, subsequently leading "iron–lipid" disturbances via modulation STAT3–HAMP–ACSL4–LPCAT3 axis. Additional bidirectional experiments conducted using MH7A AML12 cells confirm regulatory effects on targets. Collectively, our highlight association iron-mediated TGT offering guidance rational use TwHF-based therapy therapeutic potential.

Language: Английский

Citations

4
FAM98 Family Proteins Play Distinct Roles in Osteoclastogenesis and Bone Resorption DOI Creative Commons
Lei Wang, Tarun Minocha, Bhaba Krishna Das

et al.

Biology, Journal Year: 2025, Volume and Issue: 14(1), P. 45 - 45

Published: Jan. 9, 2025

There are three FAM98 family proteins (FAM98A/B/C) in humans and mice. Their physiological functions remain largely unknown. We have previously reported that Fam98a interacts with Plekhm1 murine osteoclasts lysosome trafficking/secretion bone resorption vitro. In this study, we found all Fam98 genes were expressed precursor mature osteoclasts. While the knockdown of Fam98c by a specific short-hairpin RNA (shRNA) osteoclast precursors attenuated osteoclastogenesis, depletion Fam98b an shRNA specifically disrupted trafficking phenotypes similar to shRNA-knockdown our previous study. Loss myeloid was dispensable for trabecular cortical mass mice, as well osteoclastogenesis/bone vitro, possibly due compensation increased expression Fam98a-null These findings indicate play distinct roles osteoclastogenesis function need further investigation future studies.

Language: Английский

Citations

0
Review of the anatomical basis for predicting plutonium alpha particle radiation induced osteogenic cancers DOI Creative Commons
Scott C. Miller

The Anatomical Record, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 18, 2025

Abstract Plutonium was discovered and first synthesized in the early 1940's. Several isotopes of plutonium are used nuclear technologies, 238 Pu for heat generation 239 energy production weapons. Both emit alpha particles, which pose a significant radiation hazard when incorporated into body. Alpha particles emitted during decay deposit along very short path biological tissues (≈45 μm soft tissues). Thus, defining anatomical locations these deposits is essential to identify cells at risk damage potential malignant transformation. Bone primary site deposition retention. exposures associated with increases osteogenic cancers. preferentially deposited on endosteal endocortical bone surfaces, particularly those surrounded by red versus yellow marrow. Red marrow more vascularized sinusoid network, while largely closed capillary system. Cancellous sites has greater turnover rates relatively plutonium‐related cancers than sites. The relationships particle that include osteoclasts, reversal cells, canopy osteoblasts, lining progenitors basic multicellular unit modeling remodeling reviewed. Differences distributions naturally occurring tumors humans experimental animals noted. This review emphasizes importance retention skeleton relative risks from their progenitors.

Language: Английский

Citations

0
The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivo DOI Creative Commons

Seth P. Zimmerman,

Lili B. DeGraw,

Christopher M. Counter

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 6, 2025

Abstract The microenvironment is a rich source of new cancer targets. We thus used targeted single-guide RNA library to screen panel human pancreatic lines for genes uniquely affecting tumorigenesis. Here we show inactivation the Adapter Protein complex-2 clathrin-mediated endocytosis reduces cell growth in vitro, but completely oppositely, promotes tumor vivo. In culture, loss complex transferrin and iron import required fitness. tumors, alternative transport pathways allow pro-tumor effects manifest. most sensitive case, this attributed reprogramming plasma membrane proteome, retaining integrins on surface leading Focal Adhesion Kinase phosphorylation induction proliferative signals. function tumorigenesis dependent upon microenvironment, behaving as common essential gene culture via import, suppressor tumors integrin trafficking.

Language: Английский

Citations

0