Abstract Bone homeostasis is delicately orchestrated by osteoblasts and osteoclasts. Various pathological bone loss situations result from the overactivated osteoclastogenesis. Receptor activator of nuclear factor κB ligand (RANKL)‐activated NF‐κB and MAPK pathways is vital for osteoclastogenesis. Here, we for the first time explored the effects of l ‐tetrahydropalmatine ( l ‐THP), an active alkaloid derived from corydalis, on the formation and function of osteoclasts in vitro and in vivo. In RAW264.7 cells and bone marrow monocytes cells (BMMCs), l ‐THP inhibited osteoclastic differentiation at the early stage, down‐regulated transcription level of osteoclastogenesis‐related genes and impaired osteoclasts functions. Mechanically, Western blot showed that l ‐THP inhibited the phosphorylation of P50, P65, IκB, ERK, JNK and P38, and the electrophoretic mobility shift assay (EMSA) revealed that DNA binding activity of NF‐κB was suppressed, ultimately inhibiting the expression of nuclear factor of activated T cells (NFATc1). Besides, Co‐immunoprecipitation indicated that l ‐THP blocked the interactions of RANK and TNF receptor associated factor 6 (TRAF6) at an upstream site. In vivo, l ‐THP significantly inhibited ovariectomy‐induced bone loss and osteoclastogenesis in mice. Collectively, our study demonstrated that l ‐THP suppressed osteoclastogenesis by blocking RANK‐TRAF6 interactions and inhibiting NF‐κB and MAPK pathways. l ‐THP is a promising agent for treating osteoclastogenesis‐related diseases such as post‐menopausal osteoporosis.
Objective
To explore the efficacy of open reduction and internal fixation in the treatment of senile osteoporotic ankle fractures.
Methods
A retrospective case series study was conducted to analyze the data of 26 elderly patients with osteoporotic ankle fractures which all caused by sprain from June 2012 to June 2018 in Changhai Hospital, including 10 male and 16 female patients aged from 60 to 93 years (mean, 69.72 years). In these 26 patients, three had medial malleolus fractures, four had lateral malleolus fractures, six had double ankle fractures and 13 had cotton's fractures. According to the Lauge-Hansen type, all 26 patients can be classified into four types: 5 with supination external rotation type, 4 supination adduction type, 16 with pronation-external rotation type and 1 with pronation abduction type. All the patients received open reduction and internal fixation. Plate fixation was used for lateral and posterior malleolus fractures, plate fixation and cannulated screws were applied to fix the comminuted posterior malleolus fracture while in the comminuted internal malleolus fracture, the steel plate was used only when needed. Early professional functional rehabilitation training and active anti-osteoporosis treatment were applied. All the operation time and bleeding volume were recorded, and the reduction of fracture plus the healing of wounds were observed. At last follow-up, American Orthopedic Foot & Ankle Society (AOFAS) Ankle Hindfoot Scale was used to evaluate the treatment effect and the Visual Analogue Scale (VAS)to evaluate the therapeutic effect and the subjective satisfaction of the patients. Complications were recorded as well.
Results
All patients were followed up for 12-48 months (mean, 23.6 months). Operation time ranged from 30 to 95 minutes (mean, 70 minutes) and bleeding volume ranged from 10 to 150 ml (mean, 70 ml). All patients got satisfied reduction of fracture within 25 patients' incision healing in first intention, although one has fat liquefaction. AOFAS Ankle Hindfoot Scale improved from preoperative (84.4±10.8)points to (31.9±11.4)points at last follow-up (P<0.01), and the results were excellent in five patients, good in 17, fair in three and poor in one, with the excellent and good rate of 85%. VAS improved from preoperative(1.85±0.73)points to (9.23±0.28)points at last follow-up (P<0.01). Among 26 patients, 5 with ankle stiffness of different degree recovered after rehabilitation care, and 2 with internal malleolus fractures had bone displacement when receiving rehabilitation care, with no side effect on basic function. No serious complications such as wound infection or skin necrosis were found.
Conclusion
For osteoporotic ankle fractures in the elderly, open reduction and internal fixation can promote functional recovery and relieve pain.
Key words:
Ankle injuries; Osteoporotic fractures; Fracture fixation, internal
Abstract Psoralea corylifolia ( P corylifolia ) has been popularly applied in traditional Chinese medicine decoction for treating osteoporosis and promoting fracture healing since centuries ago. However, the bioactive natural components remain unknown. In this study, applying comprehensive two‐dimensional cell membrane chromatographic/C18 column/time‐of‐flight mass spectrometry (2D CMC/C18 column/TOFMS) system, neobavaisoflavone (NBIF), for the first time, was identified for the bioaffinity with RAW 264.7 cells membranes from the extracts of P corylifolia . Here, we revealed that NBIF inhibited RANKL‐mediated osteoclastogenesis in bone marrow monocytes (BMMCs) and RAW264.7 cells dose dependently at the early stage. Moreover, NBIF inhibited osteoclasts function demonstrated by actin ring formation assay and pit‐formation assay. With regard to the underlying molecular mechanism, co‐immunoprecipitation showed that both the interactions of RANK with TRAF6 and with c‐Src were disrupted. In addition, NBIF inhibited the phosphorylation of P50, P65, IκB in NF‐κB pathway, ERK, JNK, P38 in MAPKs pathway, AKT in Akt pathway, accompanied with a blockade of calcium oscillation and inactivation of nuclear translocation of nuclear factor of activated T cells cytoplasmic 1 (NFATc1). In vivo, NBIF inhibited osteoclastogenesis, promoted osteogenesis and ameliorated bone loss in ovariectomized mice. In summary, P corylifolia ‐derived NBIF inhibited RANKL‐mediated osteoclastogenesis by suppressing the recruitment of TRAF6 and c‐Src to RANK, inactivating NF‐κB, MAPKs, and Akt signalling pathways and inhibiting calcium oscillation and NFATc1 translocation. NBIF might serve as a promising candidate for the treatment of osteoclast‐associated osteopenic diseases.
To investigate the morphology of coronal femoral intertrochanteric fracture and its effect on reduction and internal fixation.The clinical and imaging data of 46 patients with femoral intertrochanteric fracture who met the selection criteria between August 2017 and October 2018 were reviewed. There were 15 males and 31 females; the age ranged from 62 to 91 years, with an average of 72.8 years. The causes of injury included walking falls in 35 cases, falling out of bed in 4 cases, and traffic accidents in 7 cases. The AO/Orthopaedic Trauma Association classification was type 31-A1 in 11 cases and type 31-A2 in 35 cases. All patients underwent closed reduction and internal fixation with intramedullary nails. During the operation, fracture reduction and fixation were performed according to the preoperative evaluation results. According to the patients' preoperative X-ray film and CT three-dimensional reconstruction images, the direction of the coronal fracture line of the femoral intertrochanter and the morphological characteristics of the fracture block were observed; and the coronal fracture discrimination analysis was carried out for the fractures of different AO/OTA types. The percentages of coronal femoral intertrochanteric fractures diagnosed by preoperative X-ray film and CT three-dimensional reconstruction were calculated and statistically analyzed. The fracture reduction, the position of internal fixation [measurement of tip-apex distance (TAD)]. and the reliability of internal fixation were observed after operation.X-ray film was not easy to identify coronary fracture, and the coronal fracture line and the shape of the fracture piece weree clearly visible in CT three-dimensional reconstruction images. The morphological characteristics of the coronary fracture block: in AO/OTA 31-A1 type, the fracture line extended obliquely backward from the anterior tip of the large rotor, above the small rotor with or without small rotor fracture; in AO/OTA 31-A2 type, fracture line extended obliquely backward from the anterior tip of the large rotor to below the small rotor. Thirteen cases (28.3%) of coronal fractures were found on preoperative X-ray films, and 35 cases (76.1%) were found by CT three-dimensional reconstruction, showing significant difference ( χ2=21.083, P=0.000). In AO/OTA 31-A1 type patients, the proportion of coronal fractures found by X-ray film and CT three-dimensional reconstruction was 18.2% (2/11) and 54.5% (6/11), respectively, and that in AO/OTA 31-A2 type patients was 31.4% (11/35) and 82.9% (29/35), respectively, showing significant differences ( χ2=3.143, P=0.000; χ2=20.902, P=0.000). Among the 35 patients with coronal fractures, 6 cases (17.1%) of AO/OTA 31-A1 type, 29 cases (82.9%) of AO/OTA 31-A2 type. The operation time of the patient was 80-112 minutes, with an average of 95 minutes; the intraoperative blood loss was 180-450 mL, with an average of 360 mL. There was no complication such as infection, falling pneumonia, and deep vein thrombosis of the lower extremities. At 3 days after operation, the internal fixators were all in the proper position. The TAD was 0.9-1.8 cm, with an average of 1.4 cm. All patients were followed up 14-18 months, with an average of 16 months. All the fractures healed osseously, and there was no complication such as nonunion and loosening of internal fixation.CT three-dimensional reconstruction can better identify coronal femoral intertrochanteric fractures than X-ray films, and accurately recognize and analyze the incidence and morphological characteristics of coronal fractures, which can help formulate more effective surgical strategies to promote patient recovery.研究股骨转子间冠状位骨折形态，并探讨其对复位内固定技术的影响。.回顾分析 2017 年 8 月—2018 年 10 月收治的符合选择标准的 46 例股骨转子间骨折患者临床及影像学资料。男 15 例，女 31 例；年龄 62～91 岁，平均 72.8 岁。致伤原因：行走摔伤 35 例，坠床致伤 4 例，交通事故伤 7 例。国际内固定研究协会/美国骨创伤协会（AO/OTA）分型为 31-A1 型 11 例，31-A2 型 35 例。所有患者均行闭合复位髓内钉内固定，术中根据术前评估结果进行骨折复位与固定。根据患者术前 X 线片和 CT 三维重建图像，观察股骨转子间冠状位骨折线的走向和骨折块形态特征；并对不同 AO/OTA 分型的骨折进行冠状位骨折鉴别分析。分别计算经术前 X 线片和 CT 三维重建确诊冠状位骨折的百分比，并进行统计分析。术后观察骨折复位情况、内固定位置 ［测量尖顶距（tip-apex distance TAD）］ 与内固定可靠程度。.X 线片不易识别冠状位骨折，CT 三维重建图像可清楚显示冠状位骨折线的走向和骨折块形态。冠状位骨折块的形态特点：AO/OTA 31-A1 型，骨折线从大转子顶端偏前部斜向后下延伸，在小转子以上，伴或不伴小转子骨折；AO/OTA 31-A2 型，骨折线从大转子顶端偏前部斜向后下延伸到小转子以下。术前 X 线片上确诊 13 例（28.3%）冠状位骨折，CT 三维重建确诊 35 例（76.1%），差异有统计学意义（ χ2=21.083， P=0.000）。AO/OTA 31-A1 型患者中，X 线片和 CT 三维重建确诊的冠状位骨折比例分别为 18.2%（2/11）和 54.5%（6/11），AO/OTA 31-A2 型患者分别为 31.4%（11/35）和 82.9%（29/35），差异均有统计学意义（ χ2=3.143， P=0.000； χ2=20.902， P=0.000）。在 35 例冠状位骨折患者中 AO/OTA 31-A1 型 6 例（17.1%），AO/OTA 31-A2 型 29 例（82.9%）。患者手术时间为 80～112 min，平均 95 min；术中出血量为 180～450 mL，平均 360 mL。术后无感染、坠积性肺炎及下肢深静脉血栓形成等并发症。术后 3 d 复查内固定物均在合适位置，TAD 为 0.9～1.8 cm，平均 1.4 cm。患者均获随访，随访时间 14～18 个月，平均 16 个月。骨折均获骨性愈合，无骨不连、内固定物松动等并发症发生。.CT 三维重建较 X 线片能更好识别股骨转子间冠状位骨折；准确认识和分析冠状位骨折的发生率和形态学特征，有助于制定更有效的手术策略，以促进患者恢复。.
Osteoporosis is a metabolic bone disease characterized by decreased bone density and strength due to excessive loss of bone protein and mineral content. The imbalance between osteogenesis by osteoblasts and osteoclastogenesis by osteoclasts contributes to the pathogenesis of postmenopausal osteoporosis. Estrogen withdrawal leads to increased levels of proinflammatory cytokines. Overactivated osteoclasts by inflammation play a vital role in the imbalance. Matrine is an alkaloid found in plants from the Sophora genus with various pharmacological effects, including anti-inflammatory activity. Here we demonstrate that matrine significantly prevented ovariectomy-induced bone loss and inhibited osteoclastogenesis in vivo with decreased serum levels of TRAcp5b, TNF-α, and IL-6. In vitro matrine significantly inhibited osteoclast differentiation induced by receptor activator for NF-κB ligand (RANKL) and M-CSF in bone marrow monocytes and RAW264.7 cells as demonstrated by tartrate-resistant acid phosphatase (TRAP) staining and actin-ring formation as well as bone resorption through pit formation assays. For molecular mechanisms, matrine abrogated RANKL-induced activation of NF-κB, AKT, and MAPK pathways and suppressed osteoclastogenesis-related marker expression, including matrix metalloproteinase 9, NFATc1, TRAP, C-Src, and cathepsin K. Our study demonstrates that matrine inhibits osteoclastogenesis through modulation of multiple pathways and that matrine is a promising agent in the treatment of osteoclast-related diseases such as osteoporosis.—Chen, X., Zhi, X., Pan, P., Cui, J., Cao, L., Weng, W., Zhou, Q., Wang, L., Zhai, X. Zhao, Q., Hu, H., Huang, B., Su, J. Matrine prevents bone loss in ovariectomized mice by inhibiting RANKL-induced osteoclastogenesis. FASEB J. 31, 4855–4865 (2017). www.fasebj.org
Abstract Angelica sinensis (AS; Dang Gui), a traditional Chinese herb, has for centuries been used for the treatment of bone diseases, including osteoporosis and osteonecrosis. However, the effective ingredient and underlying mechanisms remain elusive. Here, we identified guaiacol as the active component of AS by two‐dimensional cell membrane chromatography/C18 column/time‐of‐flight mass spectrometry (2D CMC/C18 column/TOFMS). Guaiacol suppressed osteoclastogenesis and osteoclast function in bone marrow monocytes (BMMCs) and RAW264.7 cells in vitro in a dose‐dependent manner. Co‐immunoprecipitation indicated that guaiacol blocked RANK‐TRAF6 association and RANK‐C‐Src association. Moreover, guaiacol prevented phosphorylation of p65, p50, IκB (NF‐κB pathway), ERK, JNK, c‐fos, p38 (MAPK pathway) and Akt (AKT pathway), and reduced the expression levels of Cathepsin K, CTR, MMP‐9 and TRAP. Guaiacol also suppressed the expression of nuclear factor of activated T‐cells cytoplasmic 1(NFATc1) and the RANKL‐induced Ca 2+ oscillation. In vivo, it ameliorated ovariectomy‐induced bone loss by suppressing excessive osteoclastogenesis. Taken together, our findings suggest that guaiacol inhibits RANKL‐induced osteoclastogenesis by blocking the interactions of RANK with TRAF6 and C‐Src, and by suppressing the NF‐κB, MAPK and AKT signalling pathways. Therefore, this compound shows therapeutic potential for osteoclastogenesis‐related bone diseases, including postmenopausal osteoporosis.
The actin-bundling protein L-plastin (LPL) mediates the resorption activity of osteoclasts, but its therapeutic potential in pathological bone loss remains unexplored. Here, we report that LPL knockout mice show increased bone mass and cortical thickness with more mononuclear tartrate-resistant acid phosphatase-positive cells, osteoblasts, CD31hiEmcnhi endothelial vessels, and fewer multinuclear osteoclasts in the bone marrow and periosteum. LPL deletion impeded preosteoclasts fusion by inhibiting filopodia formation and increased the number of preosteoclasts, which release platelet-derived growth factor-BB to promote CD31hiEmcnhi vessel growth and bone formation. LPL expression is regulated by the phosphatidylinositol 3-kinase/AKT/specific protein 1 axis in response to receptor activator of nuclear factor-κB ligand. Furthermore, we identified an LPL inhibitor, oroxylin A, that could maintain bone mass in ovariectomy-induced osteoporosis and accelerate bone fracture healing in mice. In conclusion, we showed that LPL regulates osteoclasts fusion, and targeting LPL serves as a novel anabolic therapy for pathological bone loss.
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