β-Receptor blocker enhances the anabolic effect of PTH after osteoporotic fracture

The autonomic nervous system plays a crucial role in regulating bone metabolism,with sympathetic activation stimulating bone resorption and inhibiting bone formation.We found that fractures lead to increased sympathetic tone,enhanced osteoclast resorption,decreased osteoblast formation,and thus hastened systemic bone loss in ovariectomized(OVX)mice.However,the combined administration of parathyroid hormone(PTH)and theβ-receptor blocker propranolol dramatically promoted systemic bone formation and osteoporotic fracture healing in OVX mice.The effect of this treatment is superior to that of treatment with PTH or propranolol alone.In vitro,the sympathetic neurotransmitter norepinephrine(NE)suppressed PTH-induced osteoblast differentiation and mineralization,which was rescued by propranolol.Moreover,NE decreased the PTH-induced expression of Runx2 but enhanced the expression of Rankl and the effect of PTH-stimulated osteoblasts on osteoclastic differentiation,whereas these effects were reversed by propranolol.Furthermore,PTH increased the expression of the circadian clock gene Bmal1,which was inhibited by NE-βAR signaling.Bmal1 knockdown blocked the rescue effect of propranolol on the NE-induced decrease in PTHstimulated osteoblast differentiation.Taken together,these results suggest that propranolol enhances the anabolic effect of PTH in preventing systemic bone loss following osteoporotic fracture by blocking the negative effects of sympathetic signaling on PTH anabolism.

Lumbar spine localisation method based on feature fusion

To eliminate unnecessary background information,such as soft tissues in original CT images and the adverse impact of the similarity of adjacent spines on lumbar image segmentation and surgical path planning,a two‐stage approach for localising lumbar segments is proposed.First,based on the multi‐scale feature fusion technology,a non‐linear regression method is used to achieve accurate localisation of the overall spatial region of the lumbar spine,effectively eliminating useless background information,such as soft tissues.In the second stage,we directly realised the precise positioning of each segment in the lumbar spine space region based on the non‐linear regression method,thus effectively eliminating the interference caused by the adjacent spine.The 3D Intersection over Union(3D_IOU)is used as the main evaluation indicator for the positioning accuracy.On an open dataset,3D_IOU values of 0.8339�0.0990 and 0.8559�0.0332 in the first and second stages,respectively is achieved.In addition,the average time required for the proposed method in the two stages is 0.3274 and 0.2105 s respectively.Therefore,the proposed method performs very well in terms of both pre-cision and speed and can effectively improve the accuracy of lumbar image segmentation and the effect of surgical path planning.

Cistanche Deserticola for Regulation of Bone Metabolism:Therapeutic Potential and Molecular Mechanisms on Postmenopausal Osteoporosis

Osteoporosis is a generalized disease of bone that leads to a loss of bone density and bone mass,destruction of bone microstructure,increased brittleness and therefore fracture.At present,the main treatment of Western medicine is drug therapy such as bisphosphonates,calcitriol,vitamin D,etc.However,long-term use of these drugs may bring some adverse reactions.Chinese herbal medicine Cistanche deserticola could regulate bone metabolism by promoting osteoblast activity and inhibiting osteoclast activity with low toxicity and adverse reactions.Therefore,Cistanche deserticola has attracted increasing attention for its efficacy in the prevention and treatment of osteoporosis in recent years.Here we present a literature review of the molecular pathways involved in osteoporosis and the effects of Cistanche deserticola on bone metabolism.Our objective is to clarify the mechanism of Cistanche deserticola in the treatment of osteoporosis.

Simvastatin-hydroxyapatite coatings prevent biofilm formation and improve bone formation in implant-associated infections

Implant-associated infections(IAIs)caused by biofilm formation are the most devastating complications of orthopedic surgery.Statins have been commonly and safely used drugs for hypercholesterolemia for many years.Here,we report that simvastatin-hydroxyapatite-coated titanium alloy prevents biofilm-associated infections.The antibacterial properties of simvastatin against Staphylococcus aureus and Staphylococcus epidermidis biofilms in vitro was confirmed by crystal violet staining and live-dead bacterial staining.We developed a simvastatin-and hydroxyapatite(Sim-HA)-coated titanium alloy via electrochemical deposition.Sim-HA coatings inhibited Staphylococcus aureus biofilm formation and improved the biocompatibility of the titanium alloy.Sim-HA coatings effectively prevented Staphylococcus aureus IAI in rat femurs,as confirmed by radiological assessment and histological examination.The antibacterial effects of the Sim-HA coatings were attributed to their inhibitory effects on biofilm formation,as verified by scanning electron microscopic observations and bacterial spread plate analysis.In addition,the Sim-HA coatings enhanced osteogenesis and osteointegration,as verified by micro-CT,histological evaluation,and biomechanical pull-out tests.In summary,Sim-HA coatings are promising implant materials for protection against biofilm-associated infections.

Chordomas of the upper cervical spine： clinical characteristics and surgical management of a series of 21 patients

Background Chordomas of the upper cervical spine are rare and present unique surgical challenge.This study aimed to describe the clinical characteristics and surgical management of patients with chordomas of the upper cervical spine.Methods Twenty-one patients with chordomas of the upper cervical spine who were treated in Peking University Third Hospital from January 1999 to October 2012 were retrospectively analyzed.Survival was calculated by the Kaplan-Meier method and was compared between groups using the log-rank test.Results The postoperative diagnosis was classical chordoma in 20 cases and chondroid chordoma in one case.The mean operative time was 9.5 hours （range 6-17 hours）,and the mean blood loss was 2 812 ml （range 700-4 800 ml）.There were two postoperative deaths.Unilateral vertebral artery ligation was performed in six patients,cervical nerve roots were cut in six patients,and the external branch of the superior laryngeal nerve was repaired after being cut in one case.Two patients developed postoperative velopharyngeal incompetence,and loosening of the occipitocervical screws was observed in one patient.The recurrence rate was 66.7% （10/15） after a mean follow-up period of 46.8 months （range 14-150 months）.The 5-and 10-year overall survival rates were （39.8±13.1）% and （31.9±12.7）%,respectively.There was a significant difference in survival rate between patients who underwent surgery and those who did not.Conclusion In spite of the high rates of recurrence and complications after surgical treatment of chordomas of the upper cervical spine,intralesional resection combined with adjuvant radiotherapy remains the optimal treatment to prolong survival.

High efficacy of tetra-PEG hydrogel sealants for sutureless dural closure

Advances in meticulous dural closure technique remain a great challenge for watertight dural closure in the aged society,because the cerebrospinal fluid(CSF)leakage after spinal surgery is often accompanied with the disgusting wound infection,meningitis and pseudomeningocele.Here,a tetra-poly(ethylene glycol)(PEG)-based hydrogel sealant is developed with collective advantages of facile operation,high safety,quick set time,easy injectability,favorable mechanical strength and powerful tissue adhesion for effective sutureless dural closure during the surgery procedure.Impressively,this tetra-PEG sealant can instantaneously adhere to the irregular tissue surfaces even in a liquid environment,and effectively prevent or block off the intraoperative CSF leakage for sutureless dural closure and dura regeneration.Together,this sutureless tetra-PEG adhesive can be utilized as a very promising alternative for high-efficient watertight dural closure of the clinical patients who incidentally or deliberately undergo the durotomy during the spinal surgery.

Effect of decompression range on decompression limit of cervical laminoplasty

Backgrounds:Cervical posterior decompression surgery is used to relieve ventral compression indirectly by incorporating a backward shift of the spinal cord, and this indirect decompression is bound to be limited. This study aimed to determine the decompression limit of posterior surgery and the effect of the decompression range.Methods:We retrospectively reviewed the data of 129 patients who underwent cervical open-door laminoplasty through 2008 to 2012 and were grouped as follows: C4-C7 ( n = 11), C3-C6 ( n = 61), C3-C7 ( n = 32), and C2-C7 ( n = 25). According to the relative location of spinal levels within a decompression range, the type of decompression at a given level was categorized as external decompression (ED;achieved at the levels located immediately external to the decompression range margin), internal decompression (ID;achieved at the levels located immediately internal to the decompression range margin), and central decompression (CD;achieved at the levels located in the center, far from the decompression range margin). The vertebral-cord distance (VCD) was used to evaluate the decompression limit. The C2-C7 angle and VCD on post-operative magnetic resonance images were analyzed and compared between groups. The relationship between VCD and decompression type was analyzed. Moreover, the relationship between the magnitude of the ventral compressive factor and the probability of post-operative residual compression at each level for different decompression ranges was studied. Results:There was no significant kyphosis in cervical curvature (>-5°), and there was no significant difference among the groups ( F = 2.091, P = 0.105). The VCD of a specific level depended on the decompression type of the level and followed this pattern: ED < ID < CD ( P < 0.05). The decompression type of a level was sometimes affected by the decompression range. For a given magnitude of the ventral compressive factor, the probability of residual compression was lower for the group with the larger VCD at this level. Conclusions:Our study suggests that the decompression range affected the decompression limit by changing the decompression type of a particular level. For a given cervical spinal level, the decompression limit significantly varied with decompression type as follows: ED < ID < CD. CD provided maximal decompression limit for a given level. A reasonable range of decompression could be determined based on the relationship between the magnitude of the ventral compressive factor and the decompression limits achieved by different decompression ranges.

CMTM3 suppresses bone formation and osteogenic differentiation of mesenchymal stem cells through inhibiting Erk1/2 and RUNX2 pathways

Osteoporosis,fracture,large-scale craniofacial defects and osteonecrosis are hot topics and are still underdiagnosed and undertreated in the clinic.It is urgent to understand the molecular mechanisms corresponding to the regulation of bone formation.CMTM3(CKLF-like MARVEL transmembrane domain containing 3)connects the classic chemokine to the transmembrane 4 superfamily and plays an important role in intracellular vesicles transport,EGF receptor function maintenance and cancer development.However,its expression and function in bone remain unclear.In this paper,we found that the bone volume/total volume,trabecular number,trabecular thickness and bone surface area/bone volume of Cmtm3 KO mice increased significantly,and trabecular separation and trabecular pattern factor decreased in Cmtm3 KO mice compared with WT mice by microcomputed tomography.Moreover,the bone mineral content,bone mineral density,ultimate force and stiffness were also increased in Cmtm3 KO mice.Using in vitro analysis,we showed that CMTM3 expression decreases during the differentiation of hBMSCs to osteoblasts.Knockdown of CMTM3 promoted ALP and mineralization of hBMSCs and facilitated osteoblastic differentiation with increasing RUNX2 expression.However,overexpression of CMTM3 got the opposite results.These results proved that CMTM3 was essential for osteogenic differentiation.In addition,knockdown of CMTM3 enhanced p-Erk1/2,but had no significant effect on p-Akt or p-STAT3 in hBMSCs and MC3T3-E1 cells.Taken together,our results indicated that Erk1/2 and RUNX2 pathways mediated by CMTM3 were involved in the process of osteogenic differentiation,and CMTM3 might be a new potential target in the treatment of bone formation-related disease.

聚多巴胺辅助微弧氧化后载肝素和万古霉素以提高3D打印多孔钛合金内植物的血液相容性和抗菌成骨功能（英文）

在研发多功能骨科生物材料时,抗菌能力、血液相容性、骨细胞相容性和骨整合性能是最重要的考虑因素.本文中,我们成功研发了具有良好血液相容性的抗菌、促成骨复合功能的3D打印多孔钛合金内植物.简言之,3D打印多孔钛合金支架经表面处理后具有多孔形貌的微弧氧化促成骨涂层,进而联结固定肝素钠和万古霉素.本文采用扫描电镜、X射线光电子能谱分析和傅里叶变换红外光谱学对其表面微观结构、形态和化学组成进行了表征,并用高效液相色谱法检测了其载药能力和万古霉素释放曲线.通过微生物检测、细菌死活染色和结晶紫染色,确定了其良好的抗金葡菌及菌膜性能.将人骨髓间充质干细胞在支架上培养后,用细胞计数试剂盒和细胞活性检测试剂盒检测了其增殖活性.此外,用碱性磷酸酶成活性作为标记检测了成骨细胞分化能力,通过检测活化部分凝血活酶时间、血浆凝血酶原时间和凝血酶时间,确定肝素化的支架血液相容性得到了提高.该研究结果表明,经过表面改性的3D打印多孔钛合金内植物拥有稳定的抗菌和促成骨功能,同时显现出抗凝特性.预示着其在未来能用于复杂骨缺损的定制化功能重建.

Practical strategy to construct anti-osteosarcoma bone substitutes by loading cisplatin into 3D-printed titanium alloy implants using a thermosensitive hydrogel

Surgical resection and perioperative adjuvant chemotherapy-based therapies have improved the prognosis of patients with osteosarcoma;however,intraoperative bone defects,local tumour recurrence,and chemotherapy-induced adverse effects still affect the quality of life of patients.Emerging 3D-printed titanium alloy(Ti6Al4V)implants have advantages over traditional implants in bone repair,including lower elastic modulus,lower stiffness,better bone conduction,more bone in-growth,stronger mechanical interlocking,and lager drug-loading capacity by their inherent porous structure.Here,cisplatin,a clinical first-line anti-osteosarcoma drug,was loaded into Ti6Al4V implants,within a PLGA-PEG-PLGA thermo-sensitive hydrogel,to construct bone substitutes with both anti-osteosarcoma and bone-repair functions.The optimal concentrations of cisplatin(0.8 and 1.6 mg/mL)were first determined in vitro.Thereafter,the anti-tumour effect and biosafety of the cisplatin/hydrogel-loaded implants,as well as their bone-repair potential were evaluated in vivo in tumour-bearing mouse,and bone defect rabbit models,respectively.The loading of cisplatin reduced tumour volume by more than two-thirds(from 641.1 to 201.4 mm3)with negligible organ damage,achieving better anti-tumour effects while avoiding the adverse effects of systemic cisplatin delivery.Although bone repair was hindered by cisplatin loading at 4 weeks,no difference was observed at 8 weeks in the context of implants with versus without cisplatin,indicating acceptable long-term stability of all implants(with 8.48%-10.04%bone in-growth and 16.94%-20.53%osseointegration).Overall,cisplatin/hydrogel-loaded 3D-printed Ti6Al4V implants are safe and effective for treating osteosarcoma-caused bone defects,and should be considered for clinical use.

Hierarchical Micropore/Nanorod Apatite Hybrids In-Situ Grown from 3-D Printed Macroporous Ti6Al4V Implants with Improved Bioactivity and Osseointegration

The advent of three-dimensional （3-D） printed technique provides great possibility in the fabrication of customized porous titanium （Ti） implant. However, the bioinert property of the printed Ti poses an out- standing problem. Hybrid micro-arc oxidation and hydrothermal （MAO-HT） treatment on porous metals is able to produce multi-scaled hierarchical orthopedic implant, showing great potential for surface mod- ification of 3-D printed implant. In this study, cylindrical porous Ti6Al4V （Ti64） scaffolds with pore size of 640 lure, porosity of ？3% were 3-D printed by electron beam melting process, and their surfaces were left untreated or treated by a combined MAO-HT procedure. In vitro bioactivity was tested by immer- sion in simulated body fluid for different time points. Then, 12 scaffolds in each group were implanted into the femoral condyles of New Zealand rabbit for 8 weeks. Osseointegration was evaluated by qual- itative and quantitative histological analysis, and the bone ingrowth features were probed by sequential fluorescent labeling at 3 and 6 weeks post-surgery, Following the MAO-HT treatment, the porous Ti64 scaffold was endowed with multi-scaled micro/nano-topographies and high amounts of CaP on its surface. The treated scaffold exhibited drastically enhanced apatite forming ability compared with the un- treated one. In vivo test revealed significantly that a higher amount of bone ingrowth and bone implant contact at the treated scaffold. The 2 types of scaffolds had different patterns of bone ingrowth; the treated scaffold exhibited a pattern of contact osteogenesis, by which bone formed directly on the treated implant surface, whereas bone formed distal to the implant surface of the untreated scaffold. MAO-HT treat- ment can significantly enhance the in vitro apatite-inducing ability and in vivo osseointegration capacity of 3-D porous Ti64 scaffold and may provide as a viable approach for the fabrication of bioactive 3-D printed porous implant for orthopedic applications.

Crosstalk between bone and other organs

Bone has long been considered as a silent organ that provides a reservoir of calcium and phosphorus,traditionally.Recently,further study of bone has revealed additional functions as an endocrine organ connecting systemic organs of the whole body.Communication between bone and other organs participates in most physiological and pathological events and is responsible for the maintenance of homeostasis.Here,we present an overview of the crosstalk between bone and other organs.Furthermore,we describe the factors mediating the cross-talk and review the mechanisms in the development of potential associated diseases.These connections shed new light on the pathogenesis of systemic diseases and provide novel potential targets for the treatment of systemic diseases.