Abstract
Brain health is closely linked to bone homeostasis. Skeletal aging is characterized by inadequate bone formation and marrow adiposity, but whether the brain contributes to this imbalance remains unknown. This study shows that aged brain neurons, mainly those in the hippocampus and cerebral cortex, produce excess WD repeat and FYVE domain containing 1 (WDFY1) protein and transfer it to the bone via extracellular vesicles (EVs), leading to bone-fat imbalance and osteoporosis. Increasing brain Wdfy1 expression causes premature skeletal aging. Conversely, suppressing Wdfy1 in the whole brain, hippocampus or neurons, genetically deleting neuronal Wdfy1, and selectively inhibiting neuronal EV release all improve bone health. Mechanistically, WDFY1 binds to the retromer complex to promote the endosome-to-Golgi recycling of cathepsin D and peroxiredoxin 2, thus inhibiting osteogenesis and augmenting adipogenesis. This study identifies the role of aged brain neuronal EVs as an important messenger in triggering bone-fat imbalance by transferring WDFY1 to bone.
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Data availability
This paper does not involve original code. There are restrictions to the availability of RVG-9R-siWdfy1 due to pending patent application. However, the data are available from the corresponding author upon reasonable request for the purpose of academic research and validation. Requestors may need to sign a confidentiality or material transfer agreement to prevent compromise of the pending patent.
Raw proteomic data eXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository51,52 with the dataset identifier PXD069570. All other data and materials supporting the results of this study are provided in the article, supplementary information file or source data or available from the corresponding authors upon reasonable request.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (grants 82172501 to C.-Y.C., 82125023 to H.X., 82372479 to C.-Y.C., 82072504 to H.X., 81871822 to H.X., 82101463 to G.-W.H., and 82372471 to G.-W.H.), the China National Postdoctoral Program for Innovative Talents (grant BX2021383 to C.-Y.C.), the Natural Science Foundation of Hunan Province (grants 2023JJ10094 to C.-Y.C. and 2024JJ6668 to Z.W.), the Science and Technology Innovation Program of Hunan Province (grant 2022RC1211 to C.-Y.C.), the Central South University Innovation-Driven Research Programme (grant 2023CXQD001 to C.-Y.C.), the Jiangxi Province’s Science and Technology Agency Support Program (grant 20224ACB216007 to G.-W.H.), the China Postdoctoral Science Foundation (grants 2023T160739 to S.-S.R. and 2023M733956 to S.-S.R.), the Postdoctoral Fellowship Program of CPSF (grant No. GZB20230871 to S.-S.R.), the Youth Science Foundation of Xiangya Hospital (grants 2022Q07 to S.-S.R. and 2023Q15 to Z.W.) and the Postgraduate Innovative Project of Central South University (grants 2024ZZTS0925 to H.-J.Z. and 2025ZZTS0958 to Y.-X.D.). The schematic diagram in Fig. 8b was created using BioRender, with agreement number AC28V53YLH.
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H.X., C.-Y.C. and S.-S.R. designed the study. C.-Y.C., H.X., S.-S.R., Z.W., Y.L. and X.W. wrote the manuscript. C.-Y.C., S.-S.R., C.-G.H., Y.-J.T., Y.-X.D., Y.L., X.W., H.-J.Z., J.-Y.L., T.-F.W., H.Y., H.Z. and Z.-H.H. performed the experiments or/and analyzed the data. C.-Y.C., S.-S.R. and Z.W. prepared the figures. X.-X.L., Y.Z., Z.-G.W., X.-Y.H., G.-W.H., H.-L.L., Z.-X.W. and J.C. provided technical support.
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H.X., C.-Y.C., S.-S.R., Y.L., Y.-X.D. and Z.W. are inventors of a submitted patent application related to this article. All other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Detrimental effects of AB-EVs on bone phenotypes.
a, Ex vivo fluorescent imaging of tissues from DiR-labeled YB-EVs- or AB-EVs-treated mice for 3 h by intracerebroventricular (I.C.V.) or intravenous (I.V.) injection. Scale bar: 6 mm. b–d, Femoral μCT images (b), bone microstructural parameters (c), and ultimate load (d) in vehicle-, YB-EVs-, or AB-EVs-treated 4-month-old young female mice. Scale bar: 1 mm. n = 8 (YB-EVs or AB-EVs) or 9 (vehicle) per group. e, f, qRT-PCR for Runx2 (e) and Pparγ (f), and ELISA for serum OCN (e) in 4-month-old young male mice receiving different treatments. qRT-PCR: n = 8 (YB-EVs) or 9 (vehicle or AB-EVs) per group; ELISA: n = 10 per group. g–i, Tartrate-resistant acid phosphatase (TRAP) staining images (g), osteoclast (OC) numbers (h), and ELISA for serum C-terminal telopeptides of type I collagen (CTX-I; i) in 4-month-old young male mice with different treatments. Scale bar: 50 μm. n = 10 per group. j–l, qRT-PCR for Runx2 (j) and Pparγ (k), ELISA for serum OCN (j) and CTX-I (l), and TRAP+ osteoclast numbers (l) in 15-month-old aged male mice with different treatments. n = 9 (qRT-PCR) or 10 (ELISA and TRAP) per group. m, n, Representative images (m) and quantification for the mean intensity (n) of the Dil (red)-labeled YB-EVs and AB-EVs in BMSCs. Scale bar: 50 μm. n = 5 per group. Data are mean ± SD. Statistics: one-way ANOVA with Bonferroni post hoc test (c–f, h, i, and n); unpaired, two-tailed Student’s t-test (j–l).
Extended Data Fig. 2 Plasma EVs derived from aged people inhibit osteogenesis and promote adipogenesis of BMSCs.
a, b, ARS and ORO staining images (a) and quantification of ARS+ and ORO+ areas (b) in BMSCs treated with vehicle or plasma EVs from aged or young people (A-Pla-EVs or Y-Pla-EVs) under osteogenic or adipogenic induction. Scale bar: 200 μm (ARS) or 100 μm (ORO). n = 3 per group. Data are mean ± SD. Statistics: one-way ANOVA with Bonferroni post hoc test (b).
Extended Data Fig. 3 Effects of different doses of WDFY1 on osteoclast formation.
a, b, TRAP staining images of RAW264.7 cells receiving different treatments under osteoclastic induction (a) and quantification of osteoclast numbers per well in a 48-well plate (b). Scale bar: 50 μm. n = 3 per group. Data are mean ± SD. Statistics: one-way ANOVA with Bonferroni post hoc test (b).
Extended Data Fig. 4 Effects of brain Wdfy1 overexpression or downregulation on osteogenesis, adipogenesis, and inflammation.
a–d, qRT-PCR for Runx2 (a) and Pparγ (b) expression in femur tissues, and ELISA for serum OCN (c) and pro-inflammatory factors including interleukin-1α (IL-1α), IL-1β, IL-6, and tumor necrosis factor α (TNF-α) (d) in 4-month-old young female mice treated with AAV2-Con or AAV2-Wdfy1 by intracerebroventricular injection. n = 14 (AAV2-Con) or 10 (AAV2-Wdfy1) per group. e–h, qRT-PCR for Runx2 (e) and Pparγ (f) expression in femur tissues, and ELISA for serum OCN (g) and pro-inflammatory factors (h) in 15-month-old male mice treated with AAV2-shCon or AAV2-shWdfy1. n = 6 per group. Data are mean ± SD. Statistics: unpaired, two-tailed Student’s t-test.
Extended Data Fig. 5 Hippocampal Wdfy1 overexpression or downregulation alters bone phenotypes and the bone metabolism-regulatory role of Ser-EVs.
a, b, Femoral μCT images (a) and bone microstructural parameters (b) in AAV2-Con- or AAV2-Wdfy1-treated 4-month-old young female mice, and from AAV2-shCon- or AAV2-shWdfy1-treated 15-month-old male mice. H.I.P: hippocampal injection. Scale bar: 1 mm. n = 10 (young) or 7 (aged) per group. c, Three-point bending test of femoral ultimate load. n = 8 (young) or 7 (aged) per group. d, qRT-PCR for femoral Runx2 expression and ELISA for serum OCN. qRT-PCR: n = 9 (young) or 7 (aged) per group. ELISA: n = 9 (young: AAV2-Con-H.I.P), 8 (young: AAV2-Wdfy1-H.I.P), or 7 (aged: both groups). e, ORO staining images and quantification of ORO+ areas in distal femurs. Scale bar: 50 μm. n = 10 (young) or 7 (aged) per group. f, qRT-PCR for femoral Pparγ expression. n = 9 (young: AAV2-Con-H.I.P), 10 (young: AAV2-Wdfy1-H.I.P), or 7 (aged: both groups). g–i, qRT-PCR for femoral Runx2 (g) and Pparγ (h), and ELISA for serum OCN (g) and CTX-I (i) in vehicle- or WDFY1-treated 4-month-old young female mice by intramedullary injection. n = 9 (qRT-PCR for Runx2 in WDFY1 group) or 10 (others) per group. j–l, Femoral μCT images (j), bone microstructural parameters (k), and ultimate load (l) in 4-month-old young female mice treated with Ser-EVs from different groups. Scale bar: 1 mm. n = 10 per group. Data are mean ± SD. Statistics: unpaired, two-tailed Student’s t-test (b–i, k, and l).
Extended Data Fig. 6 Neuronal Wdfy1 deletion increases osteogenesis, decreases adipogenesis, suppresses inflammation, and downregulates AB-EVs’ function in aged mice.
a, Co-staining for GFAP/WDFY1, IBA1/WDFY1, and MBP/WDFY1 in the hippocampus and cerebral cortex from 18-month-old aged mice. Scale bar: 50 μm. b, Schematic diagram of the targeting strategy for generating mice bearing the conditional Wdfy1 allele, with exon 2 flanked by loxP sites. c, Representative PCR gels showing genotyping for the loxP site (left), Camk2a-CreERT2 (middle), and Map2-CreERT2 (right) alleles across the different mouse lines. d–g, qRT-PCR for femoral Runx2 (d) and Pparγ (e), and ELISA for serum OCN (d), CTX-I (f), and pro-inflammatory factors (IL-1α, IL-1β, IL-6, and TNF-α; g) in mice of different genotypes receiving tamoxifen at 15-month-old and left for 2 months. n = 6 (Wdfy1fl/fl and Camk2a-CreERT2; Wdfy1fl/fl) or 8 (Map2-CreERT2; Wdfy1fl/fl) per group. h–k, Levels of hematological and organ function parameters including hemoglobin and red blood cells (h), neutrophil and lymphocyte percentages (i), and indicators of liver (j) or kidney (k) function. ALT: alanine transaminase; AST: aspartate aminotransferase; CREA: creatinine; BUN: blood urea nitrogen. n = 6 (Wdfy1fl/fl and Camk2a-CreERT2; Wdfy1fl/fl) or 8 (Map2-CreERT2; Wdfy1fl/fl) per group. l, m, ARS and ORO staining images (l) and quantification of ARS+ and ORO+ areas (m) in BMSCs with different treatments. Scale bar: 200 μm (ARS) or 100 μm (ORO). n = 3 per group. Data are mean ± SD. Statistics: one-way ANOVA with Bonferroni post hoc test (c–k and m).
Extended Data Fig. 7 Inhibition of neuronal EV release in aged mice increases osteogenesis, decreases adipogenesis, and impairs AB-EVs’ function.
a, Schematic diagram of the targeting strategy for generating mice bearing the floxed Rab27b allele, with exon 4 flanked by loxP sites. b, Representative PCR gels showing genotyping for the loxP site (up) and Map2-CreERT2 (bottom) alleles across the different mouse lines. c–e, qRT-PCR for femoral Runx2 (c) and Pparγ (d), and ELISA for serum OCN (c) and CTX-I (e) in Rab27bfl/fl and Map2-CreERT2; Rab27fl/fl mice receiving tamoxifen at 15-month-old and left for 2 months. n = 8 (all parameters in Rab27bfl/fl mice), 9 (Pparγ in Map2-CreERT2; Rab27fl/fl mice), or 10 (other parameters in Map2-CreERT2; Rab27fl/fl mice) per group. f, Protein contents of AB-EVs normalized to brain weight in the indicated mouse lines. n = 5 per group. g, Western blotting for WDFY1 levels in AB-EVs from mice of the indicated genotypes. n = 3 per group. h, i, ARS and ORO staining images (h) and quantification of ARS+ and ORO+ areas (i) in BMSCs receiving different treatments. Scale bar: 200 μm (ARS) or 100 μm (ORO). n = 3 per group. Data are mean ± SD. Statistics: unpaired, two-tailed Student’s t-test (c–f, and i).
Extended Data Fig. 8 Selectively suppressing neuronal Wdfy1 expression enhances osteogenesis and reduces adipogenesis.
a–c, qRT-PCR for Runx2 (a) and Pparγ (b) expression in femur tissues and ELISA for serum OCN (a) and CTX-I (c) in 16-month-old aged male mice treated with RV-MAT-9R-siCon, RV-MAT-9R-siWdfy1, RVG-9R-siCon, or RVG-9R-siWdfy1. n = 7 (RVG-9R-siWdfy1), 8 (RV-MAT-9R-siWdfy1), or 9 (RV-MAT-9R-siCon and RVG-9R-siCon groups). Data are mean ± SD. Statistics: two-way ANOVA with Bonferroni post hoc test.
Extended Data Fig. 9 WDFY1 exerts harmful effects on bone independent of TLR3/4 signaling.
a, b, Femoral μCT images (a) and quantification of Tb. BV/TV, Tb. N, Tb. Th, and Ct. Th (b) in 12-month-old Tlr3−/− male mice treated with AAV2-Con or AAV2-Wdfy1. Scale bar: 1 mm. n = 9 (AAV2-Con) or 10 (AAV2-Wdfy1) per group. c, d, Femoral μCT images (c) and quantification of Tb. BV/TV, Tb. N, Tb. Th, and Ct. Th (d) in 12-month-old Tlr4−/− male mice treated with AAV2-Con or AAV2-Wdfy1. Scale bar: 1 mm. n = 6 (AAV2-Con) or 7 (AAV2-Wdfy1) per group. Data are mean ± SD. Statistics: unpaired, two-tailed Student’s t-test (b and d).
Extended Data Fig. 10 WDFY1 binds to the retromer VPS proteins independent of the FYVE domain.
a, Direct binding between WDFY-Flag and four VPS proteins (VPS29-His, VPS26A-His, VPS26B-His, and VPS35-His) determined by anti-Flag-pull-down assay. b, Western blot analysis of Flag and WDFY1 expression in CHO cells transfected with the plasmids carrying full-length Wdfy1, one or several WD domains-deleted (ΔWD) mutant Wdfy1, or ΔFYVE mutant Wdfy1. c, Co-immunoprecipitation of full-length WDFY1-Flag or ΔFYVE mutant WDFY1-Flag with four VPS proteins after transfection of plasmids into CHO cells.
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Differentially expressed proteins between AB-EVs and YB-EVs.
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Proteins differentially pulled down by WDFY1-Flag compared to controls.
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Chen, CY., Wang, Z., Hong, CG. et al. Brain neuron-derived WDFY1 induces bone loss. Nat Aging 6, 329–348 (2026). https://doi.org/10.1038/s43587-025-01032-8
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DOI: https://doi.org/10.1038/s43587-025-01032-8
