NLRP3 blockade by MCC950 suppressed osteoclastogenesis via NF-κB/c-Fos/NFATc1 signal pathway and alleviated bone loss in diabetes mellitus

AUTHORS

Guoping Cai, Xiaoting Song, Hua Luo, Gaoyuan Dai, Honghao Zhang, Dengteng Jiang, Xinhuan Lei, Haixiao Chen, Liwei Zhang

ABSTRACT

Obesity and type 2 diabetes mellitus (T2DM) are linked to osteoporosis development, with obesity being a significant risk factor for T2DM. T2DM patients with obesity exhibit a higher fracture rate and often have a poor prognosis post-fracture. To address the urgent need for understanding the mechanisms of diabetic osteoporosis (DOP), research is ongoing to explore how obesity and T2DM impact bone metabolism. The NLRP3 inflammasome has been implicated in the pathogenesis of osteoporosis, and MCC950, an NLRP3 inflammasome inhibitor, has shown promise in various diseases but its role in osteoporosis remains unexplored. In this study, BMMs and BMSCs were isolated and cultured to investigate the effects of MCC950 on bone metabolism, and DOP model was used to evaluate the efficacy of MCC950 in vivo. The study demonstrated that MCC950 treatment inhibited osteoclast differentiation, reduced bone resorption capacity in BMMs without suppression for osteoblast differentiation from BMSCs. Additionally, MCC950 suppressed the activation of the NF-κB signaling pathway and downregulated key factors associated with osteoclast differentiation. Additionally, MCC950 alleviated bone loss in DOP mouse. These findings suggest that MCC950, by targeting the NLRP3 inflammasome, may have a protective role in preventing osteoporosis induced by T2DM with obesity. The study highlights the potential therapeutic implications of MCC950 in managing diabetic osteoporosis and calls for further research to explore its clinical application in high-risk patient populations.

Bone canonical Wnt signaling is downregulated in type 2 diabetes and associates with higher advanced glycation end-products (AGEs) content and reduced bone strength

AUTHORS

Giulia Leanza, Francesca Cannata, Malak Faraj, Claudio Pedone, Viola Viola, Flavia Tramontana, Niccolò Pellegrini, Gianluca Vadalà, Alessandra Piccoli, Rocky Strollo, Francesca Zalfa, Alec T Beeve, Erica L Scheller, Simon Y Tang, Roberto Civitelli, Mauro Maccarrone, Rocco Papalia, Nicola Napoli

ABSTRACT

Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes (SOST and RUNX2) and advanced glycation end-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D (T2D 0.249% [0.156–0.366]) vs non-diabetic subjects 0.352% [0.269–0.454]; p=0.053, as well as reduced bone strength (T2D 21.60 MPa [13.46–30.10] vs non-diabetic subjects 76.24 MPa [26.81–132.9]; p=0.002). We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p<0.0001), and GSK3B (p=0.0456) were higher, while collagen (COL1A1) was lower in T2D (p=0.0482). AGEs content was associated with SOST and WNT5A (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with LEF-1 and COL1A1 (r=–0.7500, p=0.0255; r=–0.9762, p=0.0004). SOST was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas WNT5A and GSK3B were only correlated with glycemic control (r=0.5589, p=0.0037; r=0.4901, p=0.0051). Finally, Young’s modulus was negatively correlated with SOST (r=−0.5675, p=0.0011), AXIN2 (r=−0.5523, p=0.0042), and SFRP5 (r=−0.4442, p=0.0437), while positively correlated with LEF-1 (r=0.4116, p=0.0295) and WNT10B (r=0.6697, p=0.0001). These findings suggest that Wnt signaling and AGEs could be the main determinants of bone fragility in T2D.

Homoarginine ameliorates diabetic nephropathy independent of nitric oxide synthase-3

AUTHORS

Michael D. Wetzel, Kristen Stanley, Soumya Maity, Muniswamy Madesh, Jean C. Bopassa, Alaa S. Awad

ABSTRACT

Recently we showed that homoarginine supplementation confers kidney protection in diabetic mouse models. In this study we tested whether the protective effect of homoarginine is nitric oxide synthase-3 (NOS3)-independent in diabetic nephropathy (DN). Experiments were conducted in NOS3 deficient (NOS3−/−) mice and their wild type littermate using multiple low doses of vehicle or streptozotocin and treated with homoarginine via drinking water for 24 weeks. Homoarginine supplementation for 24 weeks in diabetic NOS3−/− mice significantly attenuated albuminuria, increased blood urea nitrogen, histopathological changes and kidney fibrosis, kidney fibrotic markers, and kidney macrophage recruitment compared with vehicle-treated diabetic NOS3−/− mice. Furthermore, homoarginine supplementation restored kidney mitochondrial function following diabetes. Importantly, there were no significant changes in kidney NOS1 or NOS2 mRNA expression between all groups. In addition, homoarginine supplementation improved cardiac function and reduced cardiac fibrosis following diabetes. These data demonstrate that the protective effect of homoarginine is independent of NOS3, which will ultimately change our understanding of the mechanism(s) by which homoarginine induce renal and cardiac protection in DN. Homoarginine protective effect in DN could be mediated via improving mitochondrial function.

Incorporation of nanosized calcium silicate improved osteointegration of polyetheretherketone under diabetic conditions

AUTHORS

Rui Ma, Yongwei Li, Jialin Wang, Pei Yang, Kunzheng Wang & Wei Wang

ABSTRACT

Diabetes can impair osteoblastic functions and negatively interfere with osteointegration at the bone/implant interface. Previously, we prepared a nanosized calcium silicate (CS) incorporated-polyetheretherketone (PK) biocomposite (CS/PK) and found that the CS/PK composite exhibited enhanced osteoblast functions in vitro and osteointegration in vivo, but its bioperformance under diabetic conditions remained elusive. In this study, MC3T3-E1 cells incubated on CS/PK and PK samples were subjected to diabetic serum (DS) and normal serum (NS); cell attachment, morphology, spreading, proliferation, and osteogenic differentiation were compared to assess in vitro osteoblastic functions on the surfaces of different materials. An in vivo test was performed on diabetic rabbits implanted with CS/PK or PK implants into the cranial bone defect to assess the osteointegration ability of the implants. In vitro results showed that diabetes inhibited osteoblastic functions evidenced by impaired morphology and spreading, and decreased attachment, proliferation, and osteogenic differentiation compared with the findings under normal conditions. Notably, CS/PK ameliorated osteoblastic disfunction under diabetic conditions in vitro. In vivo results from micro-CT and histologic examinations revealed that rabbits with CS/PK implants exhibited improved osteointegration at the bone/implant interface under diabetic conditions compared with PK. Therefore, the CS/PK composite improved the impaired osteointegration induced by diabetes and is a promising orthopedic or craniofacial implant material that may obtain good clinical performance in diabetic patients.

Peri-implant defect regeneration in the diabetic pig: a preclinical study

Authors

Cornelius von Wilmowsky, Karl Andreas Schlegel, Christoph Baran, Emeka Nkenke, Friedrich Wilhelm Neukam, Tobias Moest

Abstract

Objectives
The study aims to establish a peri-implant dehiscence-type bone defect in a diabetic animal model of human bone repair and to quantify the influence of diabetes on peri-implant bone regeneration.

Material and methods
Experimental diabetes was induced in three domestic pigs by streptozotocin. Three animals served as healthy controls. After 12 months four standardized peri-implant dehiscence bone defects were surgically created in the ramus mandibulae. The animals were sacrificed after 90 days. Samples were histologically analyzed to quantify new bone height (NBH), bone-to-implant-contact (BIC), area of newly formed bone (NFB), bone-density (BD), and bone mineralization (BM) in the prepared defect (- D) and in a local control region (-L).

Results
After 90 days, diabetic animals revealed a significantly lower BIC (p=0.037) and BD (p=0.041) in the defect area (-D). NBH and BM-D differences within the groups were not significant (p>0.05). Significant more NFB was measured in the healthy control group (p=0.046). In the region of local bone BIC-L was significant less in the diabetic group (p=0.028). In the local control region BD-L and BM-L was lower in the diabetic group compared to the healthy control animals (p>0.05).

Conclusion
Histological evidence indicates impaired peri-implant defect regeneration in a diabetic animal model.

Link to Article

http://dx.doi.org/10.1016/j.jcms.2016.04.002