Dysregulation of the MACF1‐Rab14/KIF16B‐FGFR Vesicular Trafficking Axis Skews MSC Lineage Commitment in Glucocorticoid‐Induced Osteoporosis
- 1Shaanxi Provincial Key Laboratory of Ischemic Cardiovascular Disease Institute of Basic and Translational Medicine Xi'an Medical University Xi'an Shaanxi China
- 2School of Life Sciences and Technology Northwestern Polytechnical University Xi'an Shaanxi China
- 3Department of Radiology & Functional and Molecular Imaging Key Lab of Shaanxi Province Tangdu Hospital Fourth Military Medical University Xi'an Shaanxi China
Abstract
Glucocorticoid‐induced osteoporosis (GIO) is driven by a pathogenic shift in bone marrow mesenchymal stem cell (BMSC) lineage commitment from osteogenesis to adipogenesis. Here, we identify Microtubule Actin Cross‐linking Factor 1 (MACF1) as a critical regulator of MSC fate that is severely suppressed during long‐term glucocorticoid (GC) exposure. We demonstrate that MACF1 deficiency phenocopies GC‐induced marrow adiposity and bone loss. Crucially, restoring endogenous MACF1 via promoter‐targeted small activating RNA (saRNA) effectively corrects this fate bias and reverses microarchitectural deterioration in GIO mice. Mechanistically, MACF1 acts as a key facilitator of vesicular trafficking. By orchestrating the assembly of the Rab14/KIF16B complex, MACF1 drives the precise anterograde transport of Fibroblast Growth Factor Receptors (FGFRs) to the plasma membrane. GC exposure downregulates MACF1, disrupting this transport machinery and causing intracellular FGFR sequestration. This transport failure depletes functional cell‐surface FGFRs, thereby blunting osteogenic signaling and triggering the adipogenic shift. Collectively, our findings establish the MACF1‐governed intracellular trafficking network as an important determinant of FGFR spatial distribution and MSC fate, highlighting it as a promising therapeutic target for restoring bone‐fat equilibrium in GIO.
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BibTeX
@article{su2026dysregulation,
title = {{Dysregulation of the MACF1‐Rab14/KIF16B‐FGFR Vesicular Trafficking Axis Skews MSC Lineage Commitment in Glucocorticoid‐Induced Osteoporosis}},
author = {Peihong Su and Ye Tian and Fan Zhao and Jing Li and Suryaji Patil and Chunyu Zhu and Yujia Tian and Junrong Wang and Jiating Liu and Aoqi Xiang and Hua Guan and Lusha Zhang and Xiaochang Chen and Airong Qian and Qi Yu},
journal = {Advanced Science},
year = {2026},
month = aug,
doi = {10.1002/advs.77073},
url = {https://doi.org/10.1002/advs.77073},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Dysregulation of the MACF1‐Rab14/KIF16B‐FGFR Vesicular Trafficking Axis Skews MSC Lineage Commitment in Glucocorticoid‐Induced Osteoporosis
AU - Peihong Su
AU - Ye Tian
AU - Fan Zhao
AU - Jing Li
AU - Suryaji Patil
AU - Chunyu Zhu
AU - Yujia Tian
AU - Junrong Wang
AU - Jiating Liu
AU - Aoqi Xiang
AU - Hua Guan
AU - Lusha Zhang
AU - Xiaochang Chen
AU - Airong Qian
AU - Qi Yu
PY - 2026
DA - 2026/08/10
JO - Advanced Science
DO - 10.1002/advs.77073
UR - https://doi.org/10.1002/advs.77073
AB - Glucocorticoid‐induced osteoporosis (GIO) is driven by a pathogenic shift in bone marrow mesenchymal stem cell (BMSC) lineage commitment from osteogenesis to adipogenesis. Here, we identify Microtubule Actin Cross‐linking Factor 1 (MACF1) as a critical regulator of MSC fate that is severely suppressed during long‐term glucocorticoid (GC) exposure. We demonstrate that MACF1 deficiency phenocopies GC‐induced marrow adiposity and bone loss. Crucially, restoring endogenous MACF1 via promoter‐targeted small activating RNA (saRNA) effectively corrects this fate bias and reverses microarchitectural deterioration in GIO mice. Mechanistically, MACF1 acts as a key facilitator of vesicular trafficking. By orchestrating the assembly of the Rab14/KIF16B complex, MACF1 drives the precise anterograde transport of Fibroblast Growth Factor Receptors (FGFRs) to the plasma membrane. GC exposure downregulates MACF1, disrupting this transport machinery and causing intracellular FGFR sequestration. This transport failure depletes functional cell‐surface FGFRs, thereby blunting osteogenic signaling and triggering the adipogenic shift. Collectively, our findings establish the MACF1‐governed intracellular trafficking network as an important determinant of FGFR spatial distribution and MSC fate, highlighting it as a promising therapeutic target for restoring bone‐fat equilibrium in GIO.
SN - 2198-3844
ER -