高粘度の糖尿病性骨髄ニッチはTRPV2を介した細胞骨格-核メカノトランスダクションを介してBMSCの骨形成を損なう

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.