Ningyuan Sun

GDF11 decreases bone mass by stimulating osteoclastogenesis and inhibiting osteoblast differentiation

Osteoporosis is an age-related disease that affects millions of people. Growth differentiation factor 11 (GDF11) is a secreted member of the transforming growth factor beta (TGF-β) superfamily. Deletion of Gdf11 has been shown to result in a skeletal anterior–posterior patterning disorder. Here we show a role for GDF11 in bone remodelling. GDF11 treatment leads to bone loss in both young and aged mice. GDF11 inhibits osteoblast differentiation and also stimulates RANKL-induced osteoclastogenesis through Smad2/3 and c-Fos-dependent induction of Nfatc1. Injection of GDF11 impairs bone regeneration in mice and blocking GDF11 function prevents oestrogen-deficiency-induced bone loss and ameliorates age-related osteoporosis. Our data demonstrate that GDF11 is a previously unrecognized regulator of bone remodelling and suggest that GDF11 is a potential target for treatment of osteoporosis.

Vitamin D Supplementation Enhances the Fixation of Titanium Implants in Chronic Kidney Disease Mice

Vitamin D (Vit D) deficiency is a common condition in chronic kidney disease (CKD) patients that negatively affects bone regeneration and fracture healing. Previous study has shown that timely healing of titanium implants is impaired in CKD. This study aimed to investigate the effect of Vit D supplementation on implant osseointegration in CKD mice. Uremia was induced by 5/6 nephrectomy in C57BL mice. Eight weeks after the second renal surgery, animals were given 1,25(OH)2D3 three times a week intraperitoneally for four weeks. Experimental titanium implants were inserted into the distal end of femurs two weeks later. Serum measurements confirmed decreased 1,25(OH)2D levels in CKD mice, which could be successfully corrected by Vit D injections. Moreover, the hyperparathyroidism observed in CKD mice was also corrected. X-ray examination and histological sections showed successful osseointegration in these mice. Histomorphometrical analysis revealed that the bone-implant contact (BIC) ratio and bone volume (BV/TV) around the implant were significantly increased in the Vit D-supplementation group. In addition, resistance of the implant, as measured by a push-in method, was significantly improved compared to that in the vehicle group. These results demonstrate that Vit D supplementation is an effective approach to improve the fixation of titanium implants in CKD.

Effect of chronic kidney disease on the healing of titanium implants

Chronic kidney disease (CKD) has become a worldwide public health problem. However, its effect on osseointegration of dental implants is largely unknown. The aim of this study is to investigate whether CKD impairs the quality of the osseointegration of titanium implants. Uremia was induced by 5/6 nephrectomy in mice, and serum levels of BUN, FGF23, PTH and ALP were significantly increased. For in vitro tests, bone marrow mesenchymal stem cells (BMMSCs) were obtained and cultured on titanium discs. There was no significant difference in term of expression of osteogenic marker genes including Osx, Col-1, Ocn, and Opn, as quantified by qPCR. Moreover, Alizarin Red S staining showed comparable mineralized nodules formation. Histomorphometrical analysis of experimental implants inserted in the femurs of CKD mice revealed a trend of decreased BIC ratio at 2-week healing. The strength of bone-implant integration, as measured by a push-in method, was significantly lower for the CKD group at 2 weeks, although a comparable level was reached at 4 weeks. These results demonstrated that CKD only negatively affects the osseointegration of titanium implants at the early stage.

FGF23 neutralization improves bone quality and osseointegration of titanium implants in chronic kidney disease mice

Chronic kidney disease (CKD) is a worldwide health problem. Serum levels of FGF23, a phosphaturic hormone, increase at the earliest stages of CKD, and have been found to be independently associated with the mortality and morbidity of CKD patients. The purpose of this study was to evaluate whether FGF23 neutralization was able to improve bone quality and osseointegration of titanium implants. Uremia was induced by 5/6 nephrectomy in adult female mice. Postsurgery, the mice were injected with vehicle or FGF23 neutralizing antibody (5 mg/kg body weight) 3 times a week. Experimental titanium implants were inserted in the distal end of the femurs. FGF23 neutralization significantly increased serum phosphate, 1,25(OH)2D and BUN, and decreased serum PTH and FGF23, relative to vehicle-treated CKD mice. Histomorphometric analysis of the tibiae indicated that FGF23 neutralization normalized the osteoidosis observed in vehicle-treated CKD mice. Although bone-implant contact ratio remained unchanged by anti-FGF23 antibody treatment, the strength of osseointegration, as evidenced by a biomechanical push-in test, was significantly improved by FGF23 neutralization. Our findings revealed that FGF23 neutralization effectively improves bone quality and osseointegration of titanium implants in CKD mice, suggesting FGF23 as a key factor of CKD related bone diseases.

Evaluation of periodontitis and bone loss in patients undergoing hemodialysis.

BACKGROUND Chronic kidney disease has been a worldwide public health challenge and also a risk factor for oral health. The objectives of this study are to investigate the periodontal status in Chinese patients undergoing hemodialysis (HD) and assess periodontal bone loss (BL) using cone-beam computerized tomography (CBCT). METHODS The patients in the HD and control groups received periodontal and CBCT examinations in the same period. Age, sex, and HD details were obtained from a hospital database. Periodontal status was evaluated using the community periodontal index (CPI) and clinical attachment loss (AL). Periodontal BL was measured by the distance from the cemento-enamel junction to the alveolar crest using CBCT. The distance between the furcation upper and lower boundaries was considered the furcation defect. RESULTS One hundred two patients undergoing HD and 204 control patients were enrolled. As for the demographic data and number of remaining teeth for each patient, there was no significant difference between HD and control groups. The CPI and AL showed statistical differences (P <0.001). The results of periodontal BL indicated that the patients undergoing HD had significantly more BL at their mandibular first premolars and first molars than did patients in the control group (P <0.01) at every site except the disto-buccal one (P <0.05). As for the furcation defects, the distance for the patients undergoing HD was nearly double that of the patients in the control group (P <0.001). CONCLUSION Compared with the generally healthy population, periodontitis and periodontal BL were significantly more severe in the Chinese patients undergoing HD.

Effect of estrogen deficiency on the fixation of titanium implants in chronic kidney disease mice

SummaryWe established a chronic kidney disease (CKD) mouse model with estrogen deficiency and inserted titanium implants into the femur of such mice to investigate the fixation of the implants. Both the histomorphometry and implant resistance indicated that estrogen deficiency impaired the fixation of titanium implants inserted into such mice.IntroductionCKD has been regarded as a worldwide public health problem. Estrogen is a critical factor for both renal protection and bone remodeling. A previous study demonstrated that CKD impairs the early healing of titanium implants. However, the combined effect of estrogen deficiency and CKD on the fixation of titanium implants is largely unknown.MethodsForty 9-week-old female C57BL mice were randomly divided into sham, ovariectomy (OVX), CKD, and CKD + OVX groups. Uremia and estrogen deficiency were induced by 5/6 nephrectomy and OVX, respectively. Experimental titanium implants were inserted into the distal end of the femur. Bone-implant contact (BIC) ratio and bone volume (BV/TV) around the implants were histomorphometrically analyzed. The fixation strength of the implant was measured by a biomechanical push-in resistance test.ResultsSerum measurement confirmed a significant increase in serum blood urea nitrogen (BUN) in the CKD group, which was further increased by OVX. Estrogen deficiency led to significant decreases in the BIC ratio, BV/TV, and the push-in resistance in CKD animals. There was a significant interaction between the effects of OVX and CKD, with OVX exacerbating the effects of CKD on BIC ratio and push-in resistance.ConclusionsThe results indicated that estrogen deficiency exerts a synergistic effect with CKD and further impairs the fixation of titanium implants in CKD mice.

Inorganic polyphosphates stimulate FGF23 expression through the FGFR pathway.

Polyphosphate (polyP) is composed of linear polymers of orthophosphate residues linked by high-energy phosphoanhydride bonds. It has been reported to improve osteoblastic differentiation, stimulate periodontal tissue regeneration, and accelerate bone repair. The aim of this study was to evaluate the effect of polyP on the expression of FGF23, a hormone secreted mostly be mature osteoblasts and osteocytes. In this study, different types of polyP were synthesized and co-cultured with osteoblast-like UMR-106 cells. Real-time PCR and western blot were used to analyze the gene and protein expression of FGF23. We found that 1 mM polyP was able to increase FGF23 expression after 4 h, reaching a peak after 12-24 h, with expression decreasing by 48 h. We also found that polyP could activate the FGFR pathway, as evidenced by increased phosphorylation of FGFR, FRS2, and Erk1/2. When FGFR signaling was inhibited by the specific inhibitor SU5402, the effect of polyP on FGF23 expression was significantly reduced. Our results indicate that polyP is able to stimulate osteoblastic FGF23 expression and that this effect is associated with activation of the FGFR pathway. These findings provide support for the clinical use of polyP by indicating a mechanism for polyP in bone regeneration.

Estrogen Deficiency Leads to Further Bone Loss in the Mandible of CKD Mice

Background Chronic kidney disease (CKD) has been regarded as a grave public health problem. Estrogen is a critical factor for both renal protection and bone remodeling. Our previous study demonstrated that CKD impairs the healing of titanium implants. The aim of this study was to investigate the effects of estrogen deficiency on the mandibular bone in CKD mice. Methods Forty eleven-week-old female C57BL mice were used in this study. Uremia and estrogen deficiency were induced by 5/6 nephrectomy and ovariectomy (OVX), respectively. After 8 weeks, the mice were sacrificed, and their mandibles were collected for micro-CT analysis and histological examination. Results All the mice survived the experimental period. Serum measurements confirmed a significant increase in BUN in the CKD group that was further increased by OVX. OVX led to significant decreases in both the BV/TV and cortical thickness of the mandibular bone in CKD mice. Conclusion In summary, our findings indicate that estrogen deficiency leads to further mandibular bone loss in CKD mice.

Ubiquitin‐specific protease USP34 controls osteogenic differentiation and bone formation by regulating BMP2 signaling

The osteogenic differentiation of mesenchymal stem cells (MSCs) is governed by multiple mechanisms. Growing evidence indicates that ubiquitin‐dependent protein degradation is critical for the differentiation of MSCs and bone formation; however, the function of ubiquitin‐specific proteases, the largest subfamily of deubiquitylases, remains unclear. Here, we identify USP34 as a previously unknown regulator of osteogenesis. The expression of USP34 in human MSCs increases after osteogenic induction while depletion of USP34 inhibits osteogenic differentiation. Conditional knockout of Usp34 from MSCs or pre‐osteoblasts leads to low bone mass in mice. Deletion of Usp34 also blunts BMP2‐induced responses and impairs bone regeneration. Mechanically, we demonstrate that USP34 stabilizes both Smad1 and RUNX2 and that depletion of Smurf1 restores the osteogenic potential of Usp34‐deficient MSCs in vitro. Taken together, our data indicate that USP34 is required for osteogenic differentiation and bone formation.