Fibronectin silencing remodels the fibrotic bone marrow niche
- 1University of Pavia
Abstract
Bone marrow (BM) fibrosis is a defining feature of Primary Myelofibrosis, yet the extracellular matrix (ECM) that sustains the fibrotic niche remains largely untargeted therapeutically. Fibronectin (FN), a key organizer of ECM architecture and growth factor signaling, accumulates in the fibrotic BM niche and correlates with disease severity. Here, we investigated whether systemic FN depletion can disrupt pathological remodeling of the BM niche. We developed a chemically modified antisense oligonucleotide targeting FN1 (FN ASO), which reduced FN expression and assembly and impaired transforming growth factor-{beta}1 (TGF-{beta}1)-induced activation of mesenchymal stromal cells. Systemic FN ASO administration efficiently depleted circulating and BM FN in mice and was well tolerated during short-term treatment. In two complementary models of BM fibrosis, FN silencing reduced FN matrix organization, stromal activation, active TGF{beta}-1, reticulin, and collagen deposition. In Jak2V617F-driven disease, transcriptomic profiling further revealed attenuation of ECM, TGF-{beta}1, and mesenchymal remodeling programs, accompanied by changes in inflammatory signaling. Collectively, these findings identify FN as an active organizer of the fibrotic BM niche and show that its systemic silencing uncouple ECM organization from profibrotic stromal signaling, providing rationale for targeting FN in myelofibrosis with broader therapeutic relevance to fibrosis-driven diseases.
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BibTeX
@misc{calledda2026fibronectin,
title = {{Fibronectin silencing remodels the fibrotic bone marrow niche}},
author = {F. R. Calledda and V. Abbonante and M. F. Testa and D. Tosi and C. Martinelli and S. Diprima and R. Gioia and U. Gianelli and C. Marty and H. Raslova and I. Plo and D. Balestra and M. Pinotti and A. Balduini and A. Malara},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.759614},
url = {https://www.biorxiv.org/content/10.64898/2026.10.16.759614v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Fibronectin silencing remodels the fibrotic bone marrow niche
AU - F. R. Calledda
AU - V. Abbonante
AU - M. F. Testa
AU - D. Tosi
AU - C. Martinelli
AU - S. Diprima
AU - R. Gioia
AU - U. Gianelli
AU - C. Marty
AU - H. Raslova
AU - I. Plo
AU - D. Balestra
AU - M. Pinotti
AU - A. Balduini
AU - A. Malara
PY - 2026
DA - 2026/10/16
PB - bioRxiv
DO - 10.64898/2026.10.16.759614
UR - https://www.biorxiv.org/content/10.64898/2026.10.16.759614v1
AB - Bone marrow (BM) fibrosis is a defining feature of Primary Myelofibrosis, yet the extracellular matrix (ECM) that sustains the fibrotic niche remains largely untargeted therapeutically. Fibronectin (FN), a key organizer of ECM architecture and growth factor signaling, accumulates in the fibrotic BM niche and correlates with disease severity. Here, we investigated whether systemic FN depletion can disrupt pathological remodeling of the BM niche. We developed a chemically modified antisense oligonucleotide targeting FN1 (FN ASO), which reduced FN expression and assembly and impaired transforming growth factor-{beta}1 (TGF-{beta}1)-induced activation of mesenchymal stromal cells. Systemic FN ASO administration efficiently depleted circulating and BM FN in mice and was well tolerated during short-term treatment. In two complementary models of BM fibrosis, FN silencing reduced FN matrix organization, stromal activation, active TGF{beta}-1, reticulin, and collagen deposition. In Jak2V617F-driven disease, transcriptomic profiling further revealed attenuation of ECM, TGF-{beta}1, and mesenchymal remodeling programs, accompanied by changes in inflammatory signaling. Collectively, these findings identify FN as an active organizer of the fibrotic BM niche and show that its systemic silencing uncouple ECM organization from profibrotic stromal signaling, providing rationale for targeting FN in myelofibrosis with broader therapeutic relevance to fibrosis-driven diseases.
ER -