Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss

Cell, Journal Year: 2024, Volume and Issue: 187(14), P. 3690 - 3711.e19

Published: June 5, 2024

Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A with a higher prevalence periodontitis gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice the heterozygous loss-of-function mutation R878H, equivalent to human hotspot R882H. Partial transplantation Dnmt3aR878H/+ bone marrow (BM) cells resulted mutant into both myeloid lymphoid lineages an elevated abundance osteoclast precursors BM osteoclastogenic macrophages periphery. recipient promoted naturally occurring aggravated experimentally induced arthritis, enhanced osteoclastogenesis, IL-17-dependent neutrophil responses, impaired regulatory T cell immunosuppressive activity. and, subsequently, were suppressed by rapamycin treatment. CHIP represents treatable state maladaptive promoting inflammatory loss.

Language: Английский

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Insights and implications of sexual dimorphism in osteoporosis

Bone Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Feb. 18, 2024

Osteoporosis, a metabolic bone disease characterized by low mineral density and deterioration of microarchitecture, has led to high risk fatal osteoporotic fractures worldwide. Accumulating evidence revealed that sexual dimorphism is notable feature osteoporosis, with sex-specific differences in epidemiology pathogenesis. Specifically, females are more susceptible than males while prone disability or death from the disease. To date, sex chromosome abnormalities steroid hormones have been proven contribute greatly osteoporosis regulating functions cells. Understanding its related complications essential for improving treatment strategies tailored women men. This literature review focuses on mechanisms underlying mainly population aging patients, chronic glucocorticoid administration, diabetes. Moreover, we highlight implications developing therapeutics preventive screening approaches Additionally, challenges translating bench research bedside treatments future directions overcome these obstacles will be discussed.

Language: Английский

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Current perspectives on the multiple roles of osteoclasts: Mechanisms of osteoclast–osteoblast communication and potential clinical implications

eLife, Journal Year: 2024, Volume and Issue: 13

Published: April 9, 2024

Bone remodeling is a complex process involving the coordinated actions of osteoblasts and osteoclasts to maintain bone homeostasis. While influence on osteoclast differentiation well established, reciprocal regulation by has long remained enigmatic. In past few years, fascinating new role for been unveiled in promoting formation facilitating osteoblast migration sites through number different mechanisms, including release factors from matrix following resorption direct cell–cell interactions. Additionally, considerable evidence shown that can secrete coupling known as clastokines, emphasizing crucial these cells maintaining Due their osteoprotective function, clastokines hold great promise potential therapeutic targets diseases. However, despite long-standing work uncover effect vivo , more substantial efforts are still required decipher mechanisms pathways behind activity order translate them into therapies. This comprehensive review provides insights our evolving understanding highlights significance remodeling, explores treatments diseases suggesting future directions field.

Language: Английский

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Unraveling the intricacies of osteoclast differentiation and maturation: insight into novel therapeutic strategies for bone-destructive diseases

Experimental & Molecular Medicine, Journal Year: 2024, Volume and Issue: 56(2), P. 264 - 272

Published: Feb. 1, 2024

Abstract Osteoclasts are the principal cells that efficiently resorb bone. Numerous studies have attempted to reveal molecular pathways leading differentiation and activation of osteoclasts improve treatment prevention osteoporosis other bone-destructive diseases. While cumulative knowledge osteoclast regulatory molecules, such as receptor activator nuclear factor-kB ligand (RANKL) factor activated T 1 (NFATc1), contributes understanding developmental progression osteoclasts, little is known about how discrete steps osteoclastogenesis modify status but not absolute number osteoclasts. The mechanisms involved in maturation those deserve special attention due their potential use establishing a more effective strategy: targeting late-phase while preserving coupled bone formation. Recent shed light on molecules govern maturation, well metabolic changes needed adapt shifting demands. This review outlines current regulation differentiation, adaptation control mechanism. Additionally, this introduces regulate thus minimally impact

Language: Английский

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The RANK–RANKL–OPG System: A Multifaceted Regulator of Homeostasis, Immunity, and Cancer

Medicina, Journal Year: 2023, Volume and Issue: 59(10), P. 1752 - 1752

Published: Sept. 30, 2023

The RANK-RANKL-OPG system is a complex signaling pathway that plays critical role in bone metabolism, mammary epithelial cell development, immune function, and cancer. RANKL ligand binds to RANK, receptor expressed on osteoclasts, dendritic cells, T other cells. promotes osteoclast differentiation activation, which leads resorption. OPG decoy inhibits its signaling. In cancer expression often increased, can lead increased resorption the development of metastases. RANKL-neutralizing antibodies, such as denosumab, have been shown be effective treatment skeletal-related events, including osteoporosis or metastases, This review will provide comprehensive overview functions cancer, together with potential therapeutic implications RANK-RANKL for management.

Language: Английский

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Pathological progression of osteoarthritis: a perspective on subchondral bone

Frontiers of Medicine, Journal Year: 2024, Volume and Issue: 18(2), P. 237 - 257

Published: April 1, 2024

Language: Английский

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The Role of Osteoprotegerin in Breast Cancer: Genetic Variations, Tumorigenic Pathways, and Therapeutic Potential

Cancers, Journal Year: 2025, Volume and Issue: 17(3), P. 337 - 337

Published: Jan. 21, 2025

Introduction: Osteoprotegerin (OPG), encoded by the TNFRSF11B gene, is linked to development of breast cancer via several pathways, including interactions with receptor activator nuclear factor-κB (RANK) ligands, apoptosis-inducing proteins like TRAIL, and genetic variations such as single nucleotide polymorphisms (SNPs), directly altering gene expression. This review aims investigate role OPG expression in cancer. Methods: A comprehensive literature search was conducted using PubMed Medline, Google Scholar, ScienceDirect. Only full-text English publications from inception September 2024 were included. Results: Studies have demonstrated that certain SNPs specifically rs3102735 rs2073618, are a higher risk development. Additionally, OPG’s function TRAIL decoy may inhibit death cells. Furthermore, serum its BRCA mutations being investigated for their potential influence on progression. found promotes tumorigenesis enhancing cell proliferation, angiogenesis, aneuploidy normal mammary epithelial Moreover, mediates tumor-promoting effects interleukin-1 beta serve biomarker risk, particularly BRCA1 mutation carriers, through dysregulated RANK signaling. Lastly, use recombinant mouse models has been exert anti-tumor effects. Conclusions: In this review, examined. multifaceted exerts TNF-related ligand (TRAIL), modulation pro-tumorigenic microenvironment survival, metastasis. dual tumor suppressor promoter serves possible therapeutic target enhance apoptosis, limit bone metastasis, modulate microenvironment. Whilst much now known, further studies necessary fully delineate OPG.

Language: Английский

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Development of a BMU-on-a-chip model based on spatiotemporal regulation of cellular interactions in the bone remodeling cycle

Materials Today Bio, Journal Year: 2025, Volume and Issue: 32, P. 101658 - 101658

Published: March 14, 2025

Language: Английский

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ACT001 improves OVX-induced osteoporosis by suppressing the NF-κB/NLRP3 signaling pathway

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: April 7, 2025

Language: Английский

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Pathophysiology of Medication‐Related Osteonecrosis of the Jaw—A Minireview

JBMR Plus, Journal Year: 2023, Volume and Issue: 7(8)

Published: June 22, 2023

Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious adverse effect antiresorptive medications administered for control osseous malignancy, osteoporosis, or other bone metabolic diseases. Despite being reported in literature two decades ago, MRONJ etiology, pathophysiology, and progression remain largely unknown, current nonoperative operative treatment strategies are mostly empirical. Several hypotheses that attempt to explain mechanisms pathogenesis have been proposed. However, none these alone able capture complex mechanistic underpinnings disease. In this minireview, we aim highlight key findings from clinical translational studies propose unifying model MRONJ. We also identify aspects disease process require further investigation suggest areas future research efforts toward calibrating methodologic approaches validating experimental findings. © 2023 The Authors.

Language: Английский

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