Aminobisphosphonates Cause Osteoblast Apoptosis and Inhibit Bone Nodule Formation In Vitro

Bisphosphonates are widely used for the treatment of bone diseases associated with increased osteoclastic bone resorption. Bisphosphonates are known to inhibit biochemical markers of bone formation in vivo, but it is unclear to what extent this is a consequence of osteoclast inhibition or a direct inhibitory effect on cells of the osteoblast lineage. In order to investigate this issue, we studied the effects of various bisphosphonates on osteoblast growth and differentiation in vitro. The aminobisphosphonates pamidronate and alendronate inhibited osteoblast growth, caused osteoblast apoptosis, and inhibited protein prenylation in osteoblasts in a dose-dependent manner over the concentration range 20-100 microM. Further studies showed that alendronate in a dose of 0.1 mg/kg inhibited protein prenylation in calvarial osteoblasts in vivo, indicating that alendronate can be taken up by osteoblasts in sufficient amounts to inhibit protein prenylation at clinically relevant doses. Pamidronate and alendronate inhibited bone nodule formation at concentrations 10-fold lower than those required to inhibit osteoblast growth. These effects were not observed with non-nitrogen-containing bisphosphonates or with other inhibitors of protein prenylation and were only partially reversed by cotreatment with a fourfold molar excess of ss-glycerol phosphate. We conclude that aminobisphosphonates cause osteoblast apoptosis in vitro at micromolar concentrations and inhibit osteoblast differentiation at nanomolar concentrations by mechanisms that are independent of effects on protein prenylation and may be due in part to inhibition of mineralization. While these results need to be interpreted with caution because of uncertainty about the concentrations of bisphosphonates that osteoblasts are exposed to in vivo, our studies clearly demonstrate that bisphosphonates exert strong inhibitory effects on cells of the osteoblast lineage at similar concentrations to those that cause osteoclast inhibition. This raises the possibility that inhibition of bone formation by bisphosphonates may be due in part to a direct inhibitory effect on cells of the osteoblast lineage.     

Alfacalcidol treatment increases bone mass from anticatabolic and anabolic effects on cancellous and cortical bone in intact female rats

It has been reported that alfacalcidol had an anticatabolic and anabolic effect on bone in ovariectomized and aged male rat models, but this has not been tested on intact female rats. The current study was to determine the effects of alfacalcidol on cancellous and cortical bone in intact female rats with or without exercise. Seventy-four, 8.5-month-old, intact female rats were orally treated with 0, 0.005, 0.025, 0.05, or 0.1 microg/kg alfacalcidol alone or in combination with raised cage (RC) exercise for 3 months. In vivo peripheral quantitative computerized tomography (pQCT) of the proximal tibial metaphyses (PTM) and ex vivo histomorphometric analyses of the PTM and tibial shaft (TX) were performed. Only the 0.1 microg alfacalcidol/kg dose proved to be anabolic. pQCT analysis showed that this dose increased total and cortical bone mineral content and density and trabecular bone mineral density. Histomorphometrically, it induced an anabolic response by increased trabecular mass and microarchitecture from stimulated cancellous bone and bone bouton formations, and suppressed bone resorption more than bone formation on the trabecular and endocortical surfaces, to produce a positive bone balance. A positive correlation between trabecular connectivity and bone bouton numbers occurred. These findings suggest alfacalcidol treatment augments bone mass by increased cancellous bone mass and improved trabecular architecture through its anticatabolic and anabolic properties in the intact adult female rat. Last, raised cage exercise alone or the combination of raised cage and alfacalcidol was no more effective than alfacalcidol alone.     

重睑术后粘连畸形及其治疗

目的 提出重睑术后粘连畸形的概念及其治疗原则，总结各种治疗方法的临床效果。方法 将本组30例重睑术后粘连畸形者的临床表现进行了分度，根据其形成特点，采用抽除缝线、眶隔脂肪瓣移位、眶隔部眼轮匝肌下移、睑板前齿轮匝肌瓣移转、自体脂肪组织游离移植和缩短上睑提肌肌健的方法治疗。结果 术后进行3个月至2年的随访，除隔部眼轮匝肌下移、睑板前眼轮匝肌瓣多转治疗效果欠佳外，其它方法均获得满意效果。结论 治疗重睑要后连畸形应在彻底松解局部粘连的基础上，根据局部条件采用隔断粘连区的方法，可以获得满意的长期效果，     

A comparative study of the bone-restorative efficacy of anabolic agents in aged ovariectomized rats

Introduction The study was designed to compare the bone anabolic effects of basic fibroblast growth factor (bFGF), a selective agonist for prostaglandin E receptor subtype EP4, and parathyroid hormone (PTH) in aged ovariectomized (OVX) rats with severe cancellous osteopenia. Methods Groups of aged OVX rats were maintained untreated for 1 year postovariectomy (15 months of age) to develop severe tibial cancellous osteopenia. These animals were then treated with bFGF or the EP4 agonist (EP4) for 3 weeks. Other groups of aged OVX rats were treated with EP4 or PTH alone for 11 weeks, or sequentially with bFGF or EP4 for 3 weeks followed by PTH for 8 weeks. Cancellous and cortical bone histomorphometry were performed in the right proximal tibial metaphysis and tibial diaphysis respectively. Results Treatment with bFGF for 3 weeks markedly increased serum osteocalcin, osteoid volume, and osteoblast and osteoid surfaces to a greater extent than EP4. Basic FGF, but not EP4 or PTH, induced formation of osteoid islands within bone marrow. EP4 stimulated cancellous bone turnover, but failed to restore lost cancellous bone in the severely osteopenic proximal tibia after 11 weeks of treatment. In contrast, EP4, much like PTH, increased cortical bone mass in the tibial diaphysis by stimulating both periosteal and endocortical bone formation. Treatment of aged OVX rats with PTH alone tended to partially reverse the severe tibial cancellous osteopenia, whereas sequential treatment with bFGF and PTH increased tibial cancellous bone mass to near the level of vehicle-treated control rats. These findings indicate that bFGF had the strongest stimulatory effect on cancellous bone formation, and was the only anabolic agent to induce formation of osteoid islands within the bone marrow of the severely osteopenic proximal tibia. Therefore, bFGF may be more effective for the reversal of severe cancellous osteopenia. PTH and EP4 increased cortical bone mass to nearly the same extent, but cancellous bone mass was greater by two-fold in PTH-treated OVX rats than in EP4-treated OVX rats. Conclusion These findings in aged OVX rats suggest that PTH is more efficacious than EP4 for augmentation of cancellous bone in the severely osteopenic, estrogen-deplete skeleton.     

NDST-1 modulates BMPR and PTHrP signaling during endochondral bone formation in a gene knockout model

GlcNAc N-deacetylase/N-sulfotransferase-1 (NDST-1), a member of the enzyme family catalyzing the first modification step in the biosynthesis of heparan sulfate (HS), was knocked out in mice to investigate its role in embryonic development. NDST-1 null mice exhibited delayed endochondral bone formation including shortened calcified zones in limbs, delayed chondrocyte and osteogenetic differentiation, and increased chondrocyte proliferation. In situ HS binding assay revealed that the binding ability of bone morphogenetic protein (BMP) -2, -4, and -6 to endogenous HS was decreased in mutant phalanges, while that of fibroblast growth factor-1 (FGF-1) was not affected. Up-regulation of BMPR-IA, Phospho-Smad1 (P-Smad1) and parathyroid-hormone related protein (PTHrP), but not the Indian hedgehog, Gli1, Gli3, Patched, and FGFR-3, was observed. Furthermore, block of BMPR signaling with noggin rescued the delayed chondrocyte hypertrophic differentiation in NDST-1 (−/−) mice and recovered the expression of both P-Smad1 and PTHrP proteins. These results suggested that NDST-1-dependent heparan sulfate might negatively modulate BMP and its downstream PTHrP signaling, and thus affect endochondral bone development.     

Influence of Rifampin on Capsule Formation Around Silicone Implants in a Rat Model

This study investigated the effect of rifampin on the thickness of capsules around silicone implants by bactericidal activity against Stapylococcus epidermidis. Silicone blocks (1 × 1 cm) were placed into pockets created for each of the 40 rats included in the study. In group 1, the operation was performed under aseptic conditions. In group 2, standard S. epidermidis was inoculated into the pocket, whereas rifampin and S. epidermidis were applied in group 3. In group 4, only rifampin was applied topically on implants. After 12 weeks, the peri-implant capsules were removed and examined under a photomicroscope and a scanning electron microscope. The mean thickness of the capsules was 63.307 μm in group 1, 111.538 μm in group 2, 43.076 μm in group 3, and 30.384 μm in group 4. The differences between groups 2 and 3 and groups 2 and 4 were found to be statistically significant (p < 0.001). Rifampin appears to be an agent for preventing peri-implant capsule formation.     

运动调控骨代谢的关键膜上受体—G蛋白偶联受体48

G蛋白偶联受体48(GPR48)作为一富含亮氨酸重复序列的膜上七次跨膜受体,其LRR结构域与R-spondin1或Norrin结合形成复合体后可作用于下游关键因子可调控骨质疏松、阿尔茨海默病、高血压等疾病发生。骨作为重要的生理学和生物力学组织,由成骨细胞(OB)和破骨细胞(OC)分别主导的骨形成和骨吸收之间的拮抗及协同调控骨组织代谢平衡。骨细胞是力学刺激敏感细胞,调节应力加载后的骨适应性反应,而运动训练对骨产生的力学刺激可翻译成结构级联性生化反应(Wnt、c AMP/PKA/Atf4、OPG/RANKL/RANK等途径稳态表达),调控骨形成和/或骨吸收。并且,GPR48通过R-spondin1可直接调控以上信号途径的激活状态。那么,GPR48能否通过下游级联信号途径从而在运动影响骨代谢中起分子介导作用呢?探究GPR48在运动影响骨代谢中的作用及其分子介导机制,希望能进一步完善运动影响骨代谢的分子机制信号网络并为骨疾病诊治提供新靶点和非药物干预方式。     

Correlation between mechanical stress by finite element analysis and 18F‐fluoride PET uptake in hip osteoarthritis patients

¹⁸F‐fluoride positron emission tomography (¹⁸F‐fluoride PET) is a functional imaging modality used primarily to detect increased bone metabolism. Increased ¹⁸F‐fluoride PET uptake suggests an association between increased bone metabolism and load stress at the subchondral level. This study therefore examined the relationship between equivalent stress distribution calculated by finite element analysis and ¹⁸F‐fluoride PET uptake in patients with hip osteoarthritis. The study examined 34 hips of 17 patients who presented to our clinic with hip pain, and were diagnosed with osteoarthritis or pre‐osteoarthritis. The hips with trauma, infection, or bone metastasis of cancer were excluded. Three‐dimensional models of each hip were created from computed tomography data to calculate the maximum equivalent stress by finite element analysis, which was compared with the maximum standardized uptake value (SUV_max) examined by ¹⁸F‐fluoride PET. The SUV_max and equivalent stress were correlated (Spearman's rank correlation coefficient ρ = 0.752), and higher equivalent stress values were noted in higher SUV_max patients. The correlation between SUV_max and maximum equivalent stress in osteoarthritic hips suggests the possibility that ¹⁸F‐fluoride PET detect increased bone metabolism at sites of stress concentration. This study demonstrates the correlation between mechanical stress and bone remodeling acceleration in hip osteoarthritis. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:78–83, 2015.     

骨质疏松症治疗药物研究进展

骨质疏松症是一种与增龄相关的代谢性骨病,主要是由成骨细胞介导的骨形成与破骨细胞介导的骨吸收之间的失衡所致.随着骨质疏松症患病率的逐年递增,如何防治骨质疏松已经成为我国重要公共健康问题.目前骨质疏松症治疗药物主要可分为促进骨形成剂和抑制骨吸收剂.本文主要就骨质疏松症治疗药物的研究进展作一综述,为临床治疗骨质疏松症提供理论...