Abstract
Diabetes patients often suffer from fractures despite normal or high bone mineral density, a phenomenon known as the diabetic bone paradox. Gao et al.1 identify AGEs as disrupting bone quality and compromising skeletal integrity in diabetic bone disease.
Diabetes patients often suffer from fractures despite normal or high bone mineral density, a phenomenon known as the diabetic bone paradox. Gao et al. identify AGEs as disrupting bone quality and compromising skeletal integrity in diabetic bone disease.
Main text
Diabetes mellitus, especially type 2 diabetes, poses complex challenges to bone health.2 Paradoxically, diabetes patients often experience fragile fractures despite normal or higher bone mineral density (BMD),3,4 a phenomenon known as the diabetic bone paradox.5 In an illuminating new study in this issue of Cell Reports Medicine, Gao et al.1 delve into the mechanisms underlying this paradox, implicating advanced glycation end products (AGEs) as key mediators of biomineralization disorder in diabetic bone disease.
Utilizing two preclinical diabetic mouse models that closely mirror clinical observations, the authors demonstrated that diabetic bones exhibited higher BMD but lower mechanical strength compared to non-diabetic controls. Detailed microstructural analyses reveal irregular mineral deposition and a disorganized collagen fibril distribution in diabetic bone.6 Significantly, the study determined that AGEs accumulate within the bones of diabetic mice, resulting in heightened non-enzymatic collagen cross-linking that impedes the critical process of intrafibrillar mineralization.
Under normal physiological conditions, collagen fibrils guide the deposition of hydroxyapatite mineral,6 with mineralization occurring both within (intrafibrillar) and outside (extrafibrillar) the fibrillar structure.7 Intrafibrillar mineralization, where mineral forms within the gaps of collagen fibrils, is especially crucial for conferring tensile strength to bone.8 The authors elucidated that in a high-glucose environment mimicking diabetes, AGE-mediated cross-linking of collagen fibrils impairs this intrafibrillar mineralization, resulting in a buildup of mineral on the fibril surface. This disordered extrafibrillar mineral deposition compromises the bone’s microstructure and mechanical integrity.
Excitingly, the study identifies a potential therapeutic strategy focused on AGEs. Guanidines, known inhibitors of AGE formation,9 were observed to significantly improve the microstructure and biomechanical strength of diabetic bone and enhance fracture healing in mouse models. By reducing pathological AGE accumulation, treatment with guanidine restored intrafibrillar mineralization and realigned disordered collagen fibrils. These discoveries underscore the potential of targeting AGEs to regulate bone mineralization and microstructure in diabetic bone disease.
The study’s illumination of the AGE-mediated mechanism underlying biomineralization disorder in diabetes provides a new lens for understanding the diabetic bone paradox. While BMD is often used as a key clinical indicator of bone health, this work underscores the critical importance of bone quality, which encompasses microstructural and material properties beyond mineral density. The aberrant mineralization patterns and collagen disruption observed in diabetic bone help explain its fragility despite normal or higher BMD.
From a broader perspective, this study underscores the complex interplay between bone’s organic matrix (primarily collagen) and its mineral components. The process of biomineralization relies on an intricate balance and precise spatial coordination between collagen and mineral.10 Disruption of this balance, as observed with AGE accumulation in diabetes, can lead to significant deterioration of bone’s mechanical integrity. Understanding and targeting the factors that regulate this collagen-mineral relationship opens new avenues for optimizing bone health.
Although the study’s findings are illuminating, further work is needed to translate this mechanistic understanding into clinical interventions. The efficacy and safety of guanidine treatment in diabetic patients will require rigorous clinical assessment. Furthermore, the long-term impacts of reducing AGEs on bone remodeling dynamics and other physiological processes warrant careful exploration.
In summary, Gao et al.1 provide compelling evidence for the role of AGEs in mediating biomineralization disorder and bone fragility in diabetes. By elucidating the AGE-collagen-mineralization axis, this research advances our understanding of the diabetic bone paradox and identifies a promising therapeutic target. The study underscores the importance of looking beyond BMD to assess bone quality and opens new avenues for developing strategies to optimize bone health in diabetes. As our population ages and the prevalence of diabetes escalates, uncovering the mechanisms of diabetic bone disease and developing effective interventions becomes increasingly vital. This research signifies a significant stride in that endeavor.
Declaration of interests
The authors declare no competing interests.
References
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