Fragile fractures are a severe complication of type 1 diabetes mellitus (T1DM), with patients experiencing a 6- to 7-fold higher fracture incidence than non-diabetic individuals [[1], [2], [3]]. This bone fragility cannot be explained solely by reduced bone mineral density; qualitative impairments in bone microarchitecture and strength are also critical factors [4]. Although insulin deficiency, hyperglycemia, and the accumulation of advanced glycation end products (AGEs) contribute to skeletal dysfunction [5], current therapies have limited efficacy in preventing bone loss in T1D, highlighting the need for mechanistic insights beyond classical metabolic factors.

Emerging evidence from bone immunology has introduced the concept of “immunoporosis,” underscoring the role of immune dysregulation in osteoporosis [6]. However, while T cells and macrophages have been studied extensively, the contribution of neutrophils—the most abundant innate immune cells—remains largely unexplored in T1D-related bone fragility.

Neutrophils can release decondensed chromatin and granular proteins to form neutrophil extracellular traps (NETs) [7,8] [9] [10]. NETs contain double-stranded DNA, histones, and granular enzymes such as neutrophil elastase, cathepsin G, and myeloperoxidase (MPO) [11,12]. These structures, composed of DNA, histones, and proteolytic enzymes, are elevated in hyperglycemic states and have been implicated in diabetes-related complications, including impaired wound healing [13,14], cardiovascular [15], and renal injury [16]. Notably, NETs can exacerbate bone erosion in rheumatoid arthritis by promoting osteoclastogenesis [17], suggesting a potential but unproven role in diabetic osteoporosis. Thus, whether NETs contribute to T1D-induced bone loss and the mechanisms by which they may impair osteogenesis remain important unanswered questions.

In this study, we hypothesized that excessive NETs accumulation disrupts osteogenesis in T1D through suppression of the fibronectin 1 (FN1)–PI3K/Akt axis. Using a streptozotocin (STZ)-induced T1D mouse model and in vitro osteoblast assays, we demonstrate that degradation of NETs by DNase I restores osteogenic capacity, highlighting a novel mechanism and a potential therapeutic strategy for diabetic bone loss.