Diabetic osteoporosis (DOP) is the leading complication continuously threatening the bone health of patients with diabetes. A key pathogenic factor in DOP is loss of osteocyte viability. However, the mechanism of osteocyte death remains unclear. Here, we identified ferroptosis, which is iron-dependent programmed cell death, as a critical mechanism of osteocyte death in murine models of DOP. The diabetic microenvironment significantly enhanced osteocyte ferroptosis in vitro, as shown by the substantial lipid peroxidation, iron overload, and aberrant activation of the ferroptosis pathway. RNA sequencing showed that heme oxygenase-1 (HO-1) expression was notably upregulated in ferroptotic osteocytes. Further findings revealed that HO-1 was essential for osteocyte ferroptosis in DOP and that its promoter activity was controlled by the interaction between the upstream NRF2 and c-JUN transcription factors. Targeting ferroptosis or HO-1 efficiently rescued osteocyte death in DOP by disrupting the vicious cycle between lipid peroxidation and HO-1 activation, eventually ameliorating trabecular deterioration. Our study provides insight into DOP pathogenesis, and our results provide a mechanism-based strategy for clinical DOP treatment.
Osteocytes, essential regulators of bone homeostasis, are embedded in the mineralized bone matrix. Given the spatial arrangement of osteocytes, bioprinting represents an ideal method to biofabricate a 3D osteocyte network with a suitable surrounding matrix similar to native bone tissue. Here, we reported a 3D bioprinted osteocyte-laden hydrogel for biomimetic mineralization in vitro with exceptional shape fidelity, a high cell density (107 cells per ml) and high cell viability (85%–90%). The bioinks were composed of biomimetic modified biopolymers, namely, gelatine methacrylamide (GelMA) and hyaluronic acid methacrylate (HAMA), with or without type I collagen. The osteocyte-laden constructs were printed and cultured in mineralization induction media. After 28 d, increased dendritic cell connections and enhanced mineralized matrix production were observed after the addition of type I collagen. These results were further confirmed by the expression of osteocyte-related genes, markers of osteocyte morphology (Connexin43 and E11/Podoplanin), markers of mineralization (dentin matrix acidic phosphoprotein 1 (Dmp1)) and the cellular response to parathyroid hormone (PTH). Moreover, the 3D bioprinting constructs outperformed the 2D monolayer culture and they were at least comparable to 3D casted hydrogels in mimicking the natural osteocyte phenotype. All results indicated that the 3D bioprinting osteocyte network shows promise for mechanistic studies and pharmaceutical screening in vitro.
Although great progress has been made in engineered bone tissues, delayed or ineffective bone regeneration remains an issue due to the lack of neural network reconstruction in their design. Therefore, an engineered bone tissue construct that mimics the ossification center microenvironment to promote innervation is proposed. Based on this, the NGF@Lap constructs are constructed through bioprinting technology, which can release nerve growth factor (NGF) for a long time and simulate the ossification center's microenvironment with high expression NGF. In vitro, NGF@Lap‐GA can promote axonal extension. Meanwhile, the NGF and Laponite from the constructs can respectively promote the expression and secretion of calcitonin gene‐related peptide (CGRP) in sensory neurons. Further, the constructs show a CGRP‐dependent osteogenic and inhibition of adipogenesis, which is mainly regulated by AMP‐activated protein kinase‐peroxisome proliferator activated receptor pathway. In vivo, the constructs increased neurovascular network density in the tissue surrounding the implant, promoted bone marrow mesenchymal stem cells osteogenic differentiation, and effectively improved bone regeneration in the cranial defect model. In conclusion, the novel tissue‐engineered bone simulates the ossification center microenvironment, promotes innervation, and has promising potential for future application in bone regeneration.
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