Background Both advanced glycation end products (AGEs) and AGE-mediated M1 macrophage polarization contribute to bone marrow mesenchymal stem cell (BMSC) dysfunction, leading to impaired bone regeneration in type 1 diabetes mellitus (T1DM). Adrenomedullin 2 (ADM2), an endogenous bioactive peptide belonging to the calcitonin gene-related peptide family, exhibits various biological activities associated with the inhibition of inflammation and reduction of insulin resistance. However, the effects and underlying mechanisms of ADM2 in AGE-induced macrophage M1 polarization, BMSC dysfunction, and impaired bone regeneration remain poorly understood. Methods The polarization of bone marrow-derived macrophages was verified using flow cytometry analysis. Alkaline phosphatase (ALP) staining, ALP activity detection, and alizarin red staining were performed to assess the osteogenesis of BMSCs. Quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, and immunofluorescence staining were used to assess polarization markers, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, and osteogenic markers. In vivo, a distraction osteogenesis (DO) rat model with T1DM was established, and tibia samples were collected at different time points for radiological, biomechanical, and histological analyses, to verify the effects of ADM2 on bone regeneration and M2 polarization under diabetic conditions. Results ADM2 treatment reversed AGE-induced M1 macrophage polarization towards the M2 phenotype, which was partially achieved by the peroxisome proliferator-activated receptor γ (PPARγ)-mediated inhibition of NF-κB signaling. The PPARγ inhibitor GW9662 significantly attenuated the effects of ADM2. Besides, ADM2 treatment improved the AGE-impaired osteogenic potential of BMSCs in vitro. Furthermore, ADM2 accelerated bone regeneration, as revealed by improved radiological and histological manifestations and biomechanical parameters, accompanied by improved M2 macrophage polarization in diabetic DO rats, and these effects were partially blocked by GW9662 administration. Conclusions These results indicate that ADM2 enhances diabetic bone regeneration during DO, by attenuating AGE-induced imbalances in macrophage polarization, partly through PPARγ/NF-κB signaling, and improving AGE-impaired osteogenic differentiation of BMSCs simultaneously. These findings reveal that ADM2 may serve as a potential bioactive factor for promoting bone regeneration under diabetic conditions, and imply that management of inflammation and osteogenesis, in parallel, may present a promising therapeutic strategy for diabetic patients during DO treatment.
Both osteogenic differentiation and the pro-angiogenic potential of bone marrow mesenchymal stem cells (BMSCs) contribute to bone regeneration during distraction osteogenesis (DO). Adrenomedullin 2 (ADM2), an endogenous bioactive peptide belonging to the calcitonin gene-related peptide family, exhibits various biological activities associated with the inhibition of inflammation and the attenuation of ischemic-hypoxic injury. However, the effects and underlying mechanisms of ADM2 in osteogenic differentiation and the pro-angiogenic potential of BMSCs, along with bone regeneration, remain poorly understood. In the present study, we found that osteogenic induction enhanced the pro-angiogenic potential of BMSCs, and ADM2 treatment further improved the osteogenic differentiation and pro-angiogenic potential of BMSCs. Moreover, the accumulation and activation of β-catenin, which is mediated by the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the activation of protein kinase B (AKT), have been shown to contribute to the effects of ADM2 on BMSCs. In vivo, ADM2 accelerated vessel expansion and bone regeneration, as revealed by improved radiological and histological manifestations and the biomechanical parameters in a rat DO model. Based on the present results, we concluded that ADM2 accelerates bone regeneration during DO by enhancing the osteogenic differentiation and pro-angiogenic potential of BMSCs, partly through the NF-κB/β-catenin and AKT/β-catenin pathways. Moreover, these findings imply that BMSC-mediated coupling of osteogenesis and angiogenesis may be a promising therapeutic strategy for DO patients.
Introduction To compare the clinical outcomes and the radiographic features between tibial condylar valgus osteotomy (TCVO) and open wedge high tibial osteotomy (OWHTO). New insight into the indication criteria for TCVO was also clarified for achieving satisfactory results. Materials and methods Sixty-three knees with medial-compartment osteoarthritis were retrospectively studied. Thirty-four knees with subluxated lateral joint and depression of the medial tibial plateau underwent TCVO and the rest underwent OWHTO. Among the 63 knees included, 27 knees with a pre-operative femorotibial angle (FTA) ≥ 185° were defined as severe varus (subgroup S, 15 in STCVO group and 12 in SHTO group). Lower limb alignment, intra-, and extra-articular congruency were evaluated according to the radiograph obtained before and 24 months after surgery. The visual analog scale (VAS) score and Hospital for Special Surgery (HSS) score were obtained to assess the clinical results. Opening angle and distance of the opening gap in each group were measured by intra-operative fluoroscopy. Results During the 2-year follow-up period, the mean HSS score increased from 70.3 to 81.4 in HTO group and 65.9 to 87.3 in TCVO group (p < 0.05). The mean VAS score decreased from 5.9 to 2.6 and 6.0 to 2.1, respectively (p < 0.01). Pre-operative FTA was restored to 172.9° in HTO group and 171.3° in TCVO group, and percentage of mechanical axis (%MA) was improved to 59.7% and 61.2%, respectively. Joint line convergence angle (JLCA) was slightly restored and medial tibial plateau depression (MTPD) was relatively the same before and after OWHTO, while these parameters improved greatly (from 6.4° to 1.2° and − 8.0° to 5.9°, p < 0.01) in TCVO group. More undercorrected knees were observed in SHTO group than STCVO group (58.3% and 13.3%, p < 0.05). Opening angle and distance of the opening gap were larger in TCVO group (19.1° and 14.0 mm) than those in OWHTO group (9.3° and 10.1 mm, p < 0.05). Conclusion Compared to OWHTO, TCVO had priority in treating advanced knee OA with intra-articular deformity. However, TCVO had a limited capacity to correct the varus angle. Besides, TCVO might be suitable for medial-compartment OA with a pre-operative FTA ≥ 185°.
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