Journal: Bone Research

Article Title: TGF-β/BMP signaling in skeletal biology: molecular mechanisms, regulatory networks, and therapeutic implications in development, regeneration, and disease

doi: 10.1038/s41413-025-00497-y

Figure Lengend Snippet: Molecular components of TGF-β signaling in bone. Canonical TGF-β signaling is mediated through the Smad-dependent pathway. Upon binding of TGF-β ligands to the type II receptor (Tgfbr2), Tgfbr2 recruits and phosphorylates the type I receptor (mainly Tgfbr1/ALK5). The activated type I receptor then phosphorylates receptor-regulated Smads (R-Smads, Smad2/3) at C-terminal SSXS motifs. Phosphorylated Smad2/3 dissociate from the receptor, form a heterotrimeric complex with Smad4, and translocate into the nucleus. Within the nucleus, this complex collaborates with lineage-specific transcription factors (e.g., Runx2, Sox9) and co-regulators (e.g., p300/CBP) to modulate the expression of target genes governing osteogenesis, bone matrix deposition, and skeletal homeostasis. In parallel, TGF-β signaling also activates non-canonical pathways, predominantly through TGF-β-activated kinase 1 (TAK1), which initiates downstream MAPK cascades (p38, JNK, ERK), which regulate osteogenic responses via both Smad-independent mechanisms and crosstalk with canonical Smad signaling. Phosphorylation (Pi) events at critical residues in receptors, Smads, and MAPKs serve as key regulatory switches, fine-tuning pathway activity and biological outcomes

Article Snippet: To fully harness TGF-β/BMP pathways for therapy, future investigations should prioritize the following key areas: (1) Mechanistic specificity: Using single-cell multi-omics and advanced imaging to decode context-dependent signaling outcomes. (2) Precision delivery: Developing tissue-targeted delivery systems (e.g., exosome-encapsulated BMPs) and gene-editing approaches (e.g., CRISPR-based ACVR1 correction in FOP). (3) Long-term safety and efficacy: Evaluating oncogenic risks from chronic TGF-β inhibition and BMP overactivation using longitudinal animal models and patient-derived organoids. (4) System-level integration: Applying AI-driven modeling to optimize combinatorial interventions and define therapeutic windows.

Techniques: Binding Assay, Expressing, Phospho-proteomics, Activity Assay

Journal: Bone Research

Article Title: TGF-β/BMP signaling in skeletal biology: molecular mechanisms, regulatory networks, and therapeutic implications in development, regeneration, and disease

doi: 10.1038/s41413-025-00497-y

Figure Lengend Snippet: Signaling network integration in osteogenesis: TGF-β/BMP crosstalk with key bone regulatory pathways. TGF-β and BMP signaling pathways form a highly interconnected regulatory network with FGF, Wnt/β-catenin, PTH/PTH1R, and MAPK cascades to coordinately orchestrate osteoblast differentiation and bone formation. PTH signaling exhibits dual functionality through PTH1R: (1) canonical Gαs/cAMP/CREB activation promotes osteogenesis, while (2) ligand-induced internalization of PTH1R-TGFβRII complexes establishes a negative feedback loop that downregulates both PTH and TGF-β signaling. TGF-β-activated Smad2/3 physically interacts with the TRAF6-TAB1-TAK1 complex (induced by RANKL stimulation), creating a molecular bridge that links osteoblast and osteoclast activities. These Smad complexes transcriptionally regulate osteogenic master regulators (e.g., Dlx5, Runx2, and Osx). BMP signaling modulates the Wnt pathway through (i) Smad-dependent upregulation of Sost (sclerostin) , and (ii) both Smad-dependent and Smad-independent (e.g., p38 MAPK) induction of Dkk1 expression. These secreted inhibitors suppress canonical Wnt signaling, thereby influencing bone mass regulation via the RANKL/OPG axis

Article Snippet: To fully harness TGF-β/BMP pathways for therapy, future investigations should prioritize the following key areas: (1) Mechanistic specificity: Using single-cell multi-omics and advanced imaging to decode context-dependent signaling outcomes. (2) Precision delivery: Developing tissue-targeted delivery systems (e.g., exosome-encapsulated BMPs) and gene-editing approaches (e.g., CRISPR-based ACVR1 correction in FOP). (3) Long-term safety and efficacy: Evaluating oncogenic risks from chronic TGF-β inhibition and BMP overactivation using longitudinal animal models and patient-derived organoids. (4) System-level integration: Applying AI-driven modeling to optimize combinatorial interventions and define therapeutic windows.

Techniques: Protein-Protein interactions, Activation Assay, Expressing

Journal: Bone Research

Article Title: TGF-β/BMP signaling in skeletal biology: molecular mechanisms, regulatory networks, and therapeutic implications in development, regeneration, and disease

doi: 10.1038/s41413-025-00497-y

Figure Lengend Snippet: Spatiotemporal regulation of TGF-β/BMP signaling networks in cartilage. TGF-β/BMP signaling pathways display distinct spatial expression profiles and engage in intricate crosstalk with other major cascades, such as IGF, WNT/β-catenin, and FGF, across different growth plate zones (resting zone, RZ; proliferating zone, PZ; hypertrophic zone, HZ; calcified zone, CZ). These signaling networks collectively regulate chondrocyte proliferation, differentiation, and maturation during endochondral ossification. A central regulatory circuit, the Ihh-PTHrP feedback axis, critically controls the pace and spatial organization of chondrocyte differentiation. Both BMP and FGF pathways interact synergistically with the Ihh-PTHrP network within the growth plate, highlighting a multi-layered regulatory architecture that ensures precise coordination of skeletal growth

Article Snippet: To fully harness TGF-β/BMP pathways for therapy, future investigations should prioritize the following key areas: (1) Mechanistic specificity: Using single-cell multi-omics and advanced imaging to decode context-dependent signaling outcomes. (2) Precision delivery: Developing tissue-targeted delivery systems (e.g., exosome-encapsulated BMPs) and gene-editing approaches (e.g., CRISPR-based ACVR1 correction in FOP). (3) Long-term safety and efficacy: Evaluating oncogenic risks from chronic TGF-β inhibition and BMP overactivation using longitudinal animal models and patient-derived organoids. (4) System-level integration: Applying AI-driven modeling to optimize combinatorial interventions and define therapeutic windows.

Techniques: Protein-Protein interactions, Expressing

Journal: Bone Research

Article Title: TGF-β/BMP signaling in skeletal biology: molecular mechanisms, regulatory networks, and therapeutic implications in development, regeneration, and disease

doi: 10.1038/s41413-025-00497-y

Figure Lengend Snippet: Multilayered negative regulation of TGF-β/BMP signaling in bone homeostasis. The TGF-β/BMP signaling pathway is precisely controlled through a multi-level inhibitory network. Extracellularly, soluble antagonists such as Noggin, Gremlin-1, and Chordin bind ligands and prevent receptor activation. Intracellularly, inhibitory Smads (I-Smads, Smad6/7) compete with receptor-activated Smads (R-Smads) for type I receptor binding and disrupt subsequent heterotrimeric complex formation with Smad4. The stability of signaling components is regulated by E3 ubiquitin ligases (e.g., Smurf1/2), which mediate K48-linked ubiquitination (Ub) and proteasomal degradation of activated R-Smads and receptors. Transcriptional control is achieved through corepressors (SnoN, Ski) that hinder Smad-DNA binding and recruit histone deacetylases (HDAC1/2) to repress osteogenic gene expression. Additional regulatory mechanisms include: (1) microRNAs (e.g., miR-21, miR-199a family) that post-transcriptionally modulate pathway components; (2) phosphatases (PPM1A, PP2A) that dephosphorylate receptors and Smads (phosphorylation, Pi)

Article Snippet: To fully harness TGF-β/BMP pathways for therapy, future investigations should prioritize the following key areas: (1) Mechanistic specificity: Using single-cell multi-omics and advanced imaging to decode context-dependent signaling outcomes. (2) Precision delivery: Developing tissue-targeted delivery systems (e.g., exosome-encapsulated BMPs) and gene-editing approaches (e.g., CRISPR-based ACVR1 correction in FOP). (3) Long-term safety and efficacy: Evaluating oncogenic risks from chronic TGF-β inhibition and BMP overactivation using longitudinal animal models and patient-derived organoids. (4) System-level integration: Applying AI-driven modeling to optimize combinatorial interventions and define therapeutic windows.

Techniques: Activation Assay, Binding Assay, Ubiquitin Proteomics, Control, Gene Expression, Phospho-proteomics

Journal: Bone Research

Article Title: TGF-β/BMP signaling in skeletal biology: molecular mechanisms, regulatory networks, and therapeutic implications in development, regeneration, and disease

doi: 10.1038/s41413-025-00497-y

Figure Lengend Snippet: Dysregulation of TGF-β/BMP signaling in osteoarthritis pathogenesis. TGF-β/BMP signaling pathway exerts cell-type-specific and often opposing roles in osteoarthritis (OA) progression. In articular chondrocytes, aberrant activation of TGF-β (particularly TGF-β3 isoform) induces pathological hypertrophy and matrix degradation by upregulating MMPs (MMP-13, ADAMTS-5) while simultaneously inducing the BMP antagonist Gremlin-1 , shifting the joint environment toward a catabolic state. In synovial fibroblasts, elevated BMP signaling enhances Smad1/5/8 phosphorylation, driving inflammation and osteophyte formation. TGF-β1 released from subchondral bone promotes aberrant angiogenesis and sensory nerve ingrowth via ALK1-Smad1/5 activation in endothelial cells, further accelerating OA progression. Cytokine crosstalk intensifies OA. IL-1β synergizes with FGFs to amplify TGF-β-mediated catabolism, while paradoxically increasing BMP2/7 expression, forming a feed-forward loop that disrupts matrix homeostasis. Macrophage polarization also modulates OA pathogenesis, M1 macrophages secrete TGF-β-activated-kinase-1 (TAK1) to promote chondrocyte dedifferentiation, while M2 macrophages produce BMP6 to stimulate compensatory matrix synthesis

Article Snippet: To fully harness TGF-β/BMP pathways for therapy, future investigations should prioritize the following key areas: (1) Mechanistic specificity: Using single-cell multi-omics and advanced imaging to decode context-dependent signaling outcomes. (2) Precision delivery: Developing tissue-targeted delivery systems (e.g., exosome-encapsulated BMPs) and gene-editing approaches (e.g., CRISPR-based ACVR1 correction in FOP). (3) Long-term safety and efficacy: Evaluating oncogenic risks from chronic TGF-β inhibition and BMP overactivation using longitudinal animal models and patient-derived organoids. (4) System-level integration: Applying AI-driven modeling to optimize combinatorial interventions and define therapeutic windows.

Techniques: Activation Assay, Phospho-proteomics, Expressing