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Review
. 2025 Aug 8;16(1):438.
doi: 10.1186/s13287-025-04543-8.

HMGB1 as an emerging key modulator of bone remodeling: a narrative review

Affiliations
Review

HMGB1 as an emerging key modulator of bone remodeling: a narrative review

Jun Tang et al. Stem Cell Res Ther. .

Abstract

Bone is a dynamic tissue that undergoes microdamage and requires remodeling to replace old bone matrix. This process demands a tight coupling between bone resorption and bone formation. Aberrant internal environment can decouple these processes, reducing bone mass and compromising mechanical properties. High mobility group box-1 (HMGB1) is a multifunctional protein binding to advanced glycosylation end product-specific receptor (RAGE) and toll-like receptors (TLRs), regulating DNA repair, cytokine production, inflammation, cell proliferation, programmed cell death (PCD). Extracellular HMGB1 serves not only as a damage-associated molecular pattern (DAMP) that promotes cytokine storms and inflammatory cascade responses but also modulates osteogenesis, osteoclastogenesis and angiogenesis. Under physiological or acute trauma conditions, HMGB1 recruits osteoblasts, osteoclasts, and various immune cells to coordinate inflammation and immune responses, clearing pathogens and promoting bone repair. However, chronic HMGB1 overrelease strengthens osteoclastogenesis and bone resorption, leading to uncoupled bone remodeling and homeostatic imbalance. Thus, HMGB1 plays indispensable roles in bone metabolism and immune regulation. Current research on its involvement in bone remodeling remains incomplete and lacks systematic elucidation. This review aims to bridge this critical knowledge gap and provide a comprehensive reference for future investigations.

Keywords: Bone remodeling; HMGB1; Inflammation.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Generative AI and AI-assisted technologies in the writing process: The authors declare that they have not use AI-generated work in this manuscript. Competing interests: The authors declare no competing interests.

Figures

None
HMGB1 orchestrates bone remodeling through four mechanisms. Firstly, HMGB1 promotes the proliferation and migration of BMSCs and osteoblasts. Under the stimulation of osteoclasts, BMSCs differentiate into osteoblasts. Secondly, HMGB1 facilitates the differentiation of BMMs to osteoclasts. Thirdly, HMGB1 stimulates angiogenic activity of ECs. Lastly, HMGB1 modulates the inflammatory response by activating and promoting the production of cytokines from immune cells, as well as regulating macrophage polarization. Due to its complex functions, HMGB1 exerts different effects in different disease contexts. For instance, in bone injury, the local increase in HMGB1 can promote bone formation and angiogenesis, accelerating bone healing. However, when the condition becomes chronic, leading to persistent and excessive production of HMGB1, it primarily manifests as increased osteoclast activity and enhanced bone resorption. Abbreviations: BMSC bone marrow stromal stem cell, BMM bone marrow-derived macrophage, EC endothelial cell, HSC hematopoietic stem cell, EPC endothelial progenitor cell, BMSC bone marrow stromal stem cell, HMGB1 High mobility group protein box 1
Fig. 1
Fig. 1
Molecular Structure of HMGB1. HMGB1 protein consists of two DNA-binding domains (A-box and B-box), as well as a C-terminus and a N-terminus. A-box has anti-inflammation function, whereas B-box stimulates inflammation process. C-terminus protects the integrity of HMGB1 during transportation. Amino acid residues 28 to 44 and 179 to 185 constitute the nuclear localization signal zone, enabling HMGB1 to bind to specific DNA structures. Cysteines at C23, C45, and C106 determine the redox state of HMGB1. Abbreviations: NLS nuclear localization signals
Fig. 2
Fig. 2
The underlying mechanism of HMGB1 regulating osteoclastogenesis. During osteogenic induction, BMSCs secrete HMGB1 into extracellular space. Interaction between RANKL and RANK leads to accumulation of ROS. ROS promotes release of HMGB1. At the same time, RANKL/RANK impels HMGB1 to bind to TNFα promoter and induce its expression. TNF and LPS promote the translocation of HMGB1 into the cytoplasm. oxLDL upregulates EGR1 expression, and the latter promotes HMGB1 to leave nucleus. CD68 assists in the extracellular transfer of HMGB1. In osteocyte, aging downregulates Cx43, reducing miR21 level and subsequently increasing PTEN. Inhibition effect of PTEN on Akt phosphorylation is abolished. Decrease of phosphorylated Akt triggers apoptosis of osteocytes. Extracellular HMGB1 binds to TLR2/4 to phosphorylate p38 and activate NFκB, thereby increasing cytokine production. The HMGB1-RAGE interaction remodels actin cytoskeleton to enhance osteoclast differentiation. Abbreviations: RAGE advanced glycosylation end product-specific receptor, TLR toll-like receptor, BMM bone marrow-derived macrophage, OCP osteoclast precursor, BMSC bone marrow mesenchymal stem cell, RANKL receptor activator of nuclear factor-κb ligand, oxLDL oxidized low-density lipoprotein, LPS lipopolysaccharide, ROS reactive oxygen species, TNF-α tumor necrosis factor-α, EGCG (−)-Epigallocatechin-3-gallate, DMF dimethyl fumarate, tBHQ tert-butylhydroquinone, HO-1 heme oxygenase-1
Fig. 3
Fig. 3
HMGB1-related osteogenic regulation. HMGB1 stimulates osteoblast migration and proliferation through RAGE/MEK pathway. HMGB1-TLR4 interaction induces phosphorylation of ERK and JNK to promote proliferation of osteoblast. Additionally, TLR4, together with TLR2, facilitates translocation of NFκB into nucleus and osteoblast migration. In the hypoxia situation, HMGB1-RAGE activates ERK/JNK MAPK pathway, leading to fibrosis of osteoblast. For BMSCs, HMGB1 facilitates their migration through p38 MAPK pathway. Abbreviations: RAGE advanced glycosylation end product-specific receptor, TLR toll-like receptor, BMSC bone marrow mesenchymal stem cell, EGFR epidermal growth factor receptor
Fig. 4
Fig. 4
HMGB1 attracts HSCs and EPCs to migrate towards the injured site, where both can differentiate into ECs. Additionally, HMGB1 can promote angiogenesis through the RAGE and TLRs on the surface of ECs. Finally, HMGB1 can also indirectly facilitate angiogenesis by stimulating the secretion of VEGF from macrophages, synovial fibroblasts, and mesoangioblasts. Abbreviations: HSC hematopoietic stem cell, EPC endothelial progenitor cell, EC endothelial cell
Fig. 5
Fig. 5
During acute bone injury, HMGB1 primarily functions to promote bone formation. Trauma leads to cellular necrosis, which passively releases HMGB1 into extracellular microenvironment. HMGB1 stimulates local angiogenesis at the injury site. In addition, HMGB1 aids in the chemotaxis and activation of immune cells, which then clear necrotic cells and bacteria from the wound, creating conditions favorable for tissue repair. Lastly, HMGB1 can also chemoattract and recruit BMSCs and osteoblasts. BMSCs differentiate into osteoblasts under the stimulation of osteoclasts, which induce new bone formation and healing. In contrast, in chronic diseases, HMGB1 mainly promotes bone resorption. HMGB1 can be passively released by apoptotic osteocytes or actively secreted by immune cells stimulated by LPS produced by bacteria. LPS and HMGB1 synergistically promote the secretion of cytokines by immune cells, inhibiting the functions of BMSCs and osteoblasts while promoting the differentiation of macrophages into osteoclasts, resulting in osteoclast activation and bone resorption. Abbreviations: BMSC bone marrow stromal stem cell, LPS Lipopolysaccharide

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