Theranostics 2021; 11(8):3796-3812. doi:10.7150/thno.50907

Research Paper

Impairment of type H vessels by NOX2-mediated endothelial oxidative stress: critical mechanisms and therapeutic targets for bone fragility in streptozotocin-induced type 1 diabetic mice

Xiao-Fan Hu1*, Geng Xiang1*, Tian-Ji Wang1*, Yu-Bo Ma2, Yang Zhang1, Ya-Bo Yan1, Xiong Zhao1, Zi-Xiang Wu1✉, Ya-Fei Feng1✉, Wei Lei1✉

1. Department of Orthopedics, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
2. Department of Dermatology and Venereology, Peking University First Hospital, Research Center for Medical Mycology, Peking University, Beijing 100034, China.
* These authors contributed equally to this work.

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Citation:
Hu XF, Xiang G, Wang TJ, Ma YB, Zhang Y, Yan YB, Zhao X, Wu ZX, Feng YF, Lei W. Impairment of type H vessels by NOX2-mediated endothelial oxidative stress: critical mechanisms and therapeutic targets for bone fragility in streptozotocin-induced type 1 diabetic mice. Theranostics 2021; 11(8):3796-3812. doi:10.7150/thno.50907. Available from https://www.thno.org/v11p3796.htm

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Abstract

Rationale: Mechanisms underlying the compromised bone formation in type 1 diabetes mellitus (T1DM), which causes bone fragility and frequent fractures, remain poorly understood. Recent advances in organ-specific vascular endothelial cells (ECs) identify type H blood vessel injury in the bone, which actively direct osteogenesis, as a possible player.

Methods: T1DM was induced in mice by streptozotocin (STZ) injection in two severity degrees. Bony endothelium, the coupling of angiogenesis and osteogenesis, and bone mass quality were evaluated. Insulin, antioxidants, and NADPH oxidase (NOX) inhibitors were administered to diabetic animals to investigate possible mechanisms and design therapeutic strategies.

Results: T1DM in mice led to the holistic abnormality of the vascular system in the bone, especially type H vessels, resulting in the uncoupling of angiogenesis and osteogenesis and inhibition of bone formation. The severity of osteopathy was positively related to glycemic levels. These pathological changes were attenuated by early-started, but not late-started, insulin therapy. ECs in diabetic bones showed significantly higher levels of reactive oxygen species (ROS) and NOX 1 and 2. Impairments of bone vessels and bone mass were effectively ameliorated by treatment with anti-oxidants or NOX2 inhibitors, but not by a NOX1/4 inhibitor. GSK2795039 (GSK), a NOX2 inhibitor, significantly supplemented the insulin effect on the diabetic bone.

Conclusions: Diabetic osteopathy could be a chronic microvascular complication of T1DM. The impairment of type H vessels by NOX2-mediated endothelial oxidative stress might be an important contributor that can serve as a therapeutic target for T1DM-induced osteopathy.

Keywords: Diabetic bone fragility, Type H vessels, Endothelial damage, Oxidative stress, NADPH oxidase 2.