# Hyperviscous Diabetic Bone Marrow Niche Impairs BMSCs Osteogenesis via TRPV2‐Mediated Cytoskeletal‐Nuclear Mechanotransduction

## TL;DR

Diabetic bone marrow becomes overly sticky, which harms stem cells' ability to form bone through a chain of mechanical signals involving TRPV2.

## Contribution

Discovers a new mechanical pathway linking ECM viscosity to impaired stem cell function via TRPV2 in diabetic bone marrow.

## Key findings

- Diabetic ECM hyperviscosity activates TRPV2, causing cytoskeletal and nuclear changes in BMSCs.
- TRPV2 inhibition restores chromatin accessibility and osteogenic potential in diabetic BMSCs.
- Mechanical signals from the ECM suppress osteogenic differentiation through chromatin condensation.

## Abstract

The compromised regenerative capacity of diabetic bone defects remains a critical clinical challenge, with pathological alterations in the bone marrow microenvironment emerging as key contributors. While mechanical signals within the marrow niche critically regulate bone regeneration, how diabetic matrix abnormalities impair bone marrow‐derived mesenchymal stem cells (BMSCs) function remains unclear. Herein, it is revealed that diabetes induces a characteristic hyperviscous state in bone marrow extracellular matrix (ECM). Through comparative mechanobiological analyses, it is demonstrated that diabetic BMSCs exhibit amplified mechanosensitivity to ECM viscosity via transient receptor potential vanilloid 2 (TRPV2) activation. This mechanotransduction cascade triggers calcium influx, which activates CaMKII and subsequently phosphorylates cofilin, thereby shifting the G‐/F‐actin equilibrium toward perinuclear F‐actin disassembly. The cytoskeletal remodeling induces nuclear envelope deformation through regulation of Lamin A/C, driving spatial rearrangement of chromatin architecture. Mechanistically, these physical nuclear changes promote perinuclear heterochromatin accumulation and enhance H3K9me3 repressive histone modification, ultimately suppressing osteogenic transcriptional programs. Importantly, TRPV2 inhibition rescued both chromatin accessibility and osteogenic potential in diabetic BMSCs. This findings establish a novel mechano‐pathological axis where diabetic ECM hyperviscosity propagates mechanical signals from cytoskeleton to chromatin through TRPV2 activation, proposing mechanomodulation as a promising therapeutic strategy for diabetic osteopathy.

Diabetic bone marrow exhibits pathological ECM hyperviscosity that activates TRPV2‐mediated Ca2⁺ influx, leading to perinuclear F‐actin disassembly, nuclear deformation, and chromatin condensation. This cytoskeletal‐nuclear decoupling suppresses osteogenic differentiation of BMSCs. By uncovering a previously unrecognized mechanical pathway linking fluid viscosity to stem cell fate, this study identifies TRPV2 as a therapeutic target to restore bone regeneration in diabetic conditions.