L'os cellulaire d'un Poisson Téléostéen ≪Anguilla anguilla L.≫

Résumé Le squelette vertébral de l'Anguille est formé d'os cellulaire: lamellaire compact ou spongieux, suivant les différentes parties de la vertèbre. Nous avons pu y mettre en évidence, chez des animaux physiologiquement normaux, les trois catégories de cellules caractéristiques de l'os des vertébrés supérieurs: ostéoblastes, osteocytes, ostéoclastes. Elles ont les mêmes fonctions que chez ces derniers, les ostéoblastes procèdent à l'élaboration du tissu osseux, alors que les ostéoclastes le détruisent; à cette résorption ostéoclastique s'ajoute une lyse périostéocytaire ou résorption périlacunaire. Les osteocytes, dans ce tissu, nous paraissent être des éléments actifs; néanmoins, leur nombre (par unité de surface) est très inférieur à celui trouvé chez les Mammifères. Le remaniement osseux résultant du jeu de l'apposition et de la résorption est important et comparable à celui existant chez l'Homme.L'os de l'Anguille est, à de nombreux points de vue, très voisin de celui des Mammifères; les Poissons n'ont pas de parathyroïdes en tant que telles mais ils sont pourvus d'autres glandes vraisemblablement impliquées dans la régulation phosphocalcique: corps ultimobranchial et corpuscules de Stannius. Notre but sera donc d'essayer de déterminer comment est réglé le métabolisme de l'os cellulaire des Téléostéens.

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Histologic study on teleost cellular bone I.

Summary The vertebral skeleton of the eel consists of cellular bone, either lamellar or spongy, depending on different parts of the vertebra. In this osseous tissue we have found, in physiologically normal animals, three categories of caracteristic cells of the bone of higher vertebrates: osteoblasts, osteocytes, osteoclasts. They have the same functions as in higher vertebrates, osteoblasts form the bone while the osteoclasts which are to be found in Howship's lacunae destroy it. In addition, a perilacunar type of bone resorption or osteocytic osteolysis can be observed. In this bone, osteocytes seem to be active cells, but the concentration of osteocytes is decidedly lower than that to be found in Mammals.The osseous remodeling produced by apposition and resorption is of the same importance as in human bone. The bone of the eel, in many ways, closely resembles that of mammals. Teleost fish do not have parathyroid glands, but their phosphocalcic regulation seems to be facilitated by the action of two endocrine glands: Ultimobranchial body and the corpuscles of Stannius.The regulation of the cellular bone metabolism of Teleostean fishes is discussed.

Nous remercions Monsieur le Professeur Baud qui nous accueille dans son laboratoire à Genève et qui nous prodigue ses conseils.     

Pan-caspase inhibition suppresses polyethylene particle-induced osteolysis

Particle-induced osteolysis is a major cause of aseptic loosening after total joint replacement. Earlier studies demonstrated apoptotic macrophages, giant cells, fibroblasts and T-lymphocytes in capsules and interface membranes of patients with aseptic hip implant loosening. The aim of the current study was to determine in a murine calvarial model of wear particle-induced osteolysis whether inhibition of apoptosis using the pan-caspase inhibitor BOC-D-FMK reduces aseptic loosening. Healthy 12-week-old male C57BL/6J mice were treated with UHMWPE particles and received a daily peritoneal injection of BOK-D-FMK, respectively only buffer at a dose of 3 mg/kg of body weight for 12 days until sacrifice. Bone resorption was measured by histomorphometry, micro CT (computed tomography) and TRAP-5b serum analysis. Apoptosis was measured using caspase-3 cleaved staining. The results demonstrated that UHMWPE particles induced stronger apoptotic reactions in macrophages and osteoblasts and increased bone resorption in non-specifically treated mice, whereas peritoneal application of BOC-D-FMK significantly counteracted these adverse particle-related effects. We think that in particle-induced osteolysis apoptosis is pathologically increased, and that failure to reduce the quantity of apoptotic bodies leads to an up-regulation of proinflammtory cytokines, which may be responsible for the induction of osteolysis. We showed for the first time in vivo that a reduction in apoptosis leads to a significant reduction in particle-induced osteolysis. Clinically, the apoptotic cascade could become an interesting novel therapeutic target to modulate particle-induced osteolysis. This is an investigation performed at the University of Duisburg-Essen, Germany.     

Extracellular Microfibrils Control Osteoblast-supported Osteoclastogenesis by Restricting TGFβ Stimulation of RANKL Production

Mutations in fibrillin-1 or fibrillin-2, the major structural components of extracellular microfibrils, cause pleiotropic manifestations in Marfan syndrome and congenital contractural arachnodactyly, respectively. We recently found that fibrillin-1 and fibrillin-2 control bone formation by regulating osteoblast differentiation through the differential modulation of endogenous TGFβ and bone morphogenetic protein signals. Here, we describe in vivo and ex vivo experiments that implicate the fibrillins as negative regulators of bone resorption. Adult Fbn2^−/− mice display a greater than normal osteolytic response to locally implanted lipopolysaccharide-coated titanium particles. Although isolated cultures of Fbn2^−/− preosteoclasts exhibited normal differentiation and activity, these features were substantially augmented when mutant or wild-type preosteoclasts were co-cultured with Fbn2^−/− but not wild-type osteoblasts. Greater osteoclastogenic potential of Fbn2^−/− osteoblasts was largely accounted for by up-regulation of the Rankl gene secondary to heightened TGFβ activity. This conclusion was based on the findings that blockade of TGFβ signaling blunts Rankl up-regulation in Fbn2^−/− osteoblasts and bones and that systemic TGFβ antagonism improves locally induced osteolysis in Fbn2^−/− mice. Abnormally high Rankl expression secondary to elevated TGFβ activity was also noted in cultured osteoblasts from Fbn1^−/− mice. Collectively our data demonstrated that extracellular microfibrils balance local catabolic and anabolic signals during bone remodeling in addition to implying distinct mechanisms of bone loss in Marfan syndrome and congenital contractural arachnodactyly.     

补骨脂抑制人工关节假体周围骨溶解的研究*

摘要目的：探讨中药补骨脂对人工关节置换术后假体周围骨溶解,假体无菌性松动的核因子资B受体活化因子配体- 核因子资B 受体活化因子受体- 骨保护素(RANKL-RANK-OPG)信号通路的作用。方法：取24 只200± 5 g雌性SD大鼠,随机分为A、B、C 组,均注射钛颗粒溶液建立骨溶解模型,术后A 组采用中药补骨脂水溶液腹腔注射,B 组采用外源性OPG 腹腔注射作为阳性对 照,C 组采用生理盐水腹腔注射作为阴性对照。给药4 周后,通过免疫组化及反转录聚合酶链反应(RT-PCR)检测各组动物体内 RANKL/RANK的表达水平变化。结果：用药4 周后,3 组12 只大鼠背部气囊均为厚壁囊腔,骨溶解模型成功建立,免疫组化及 RT-PCR 检测RANKL/RANK 均呈阳性表达。免疫组化RANKL平均光密度(AOD)值A组(0.168± 0.017)、B 组(0.147± 0.009)明显 低于C 组(0.314± 0.011),差异有统计学意义(P＜0.05);A 组、B组之间比较无明显差异。RANK AOD值测定A组(0.172± 0.015)、 B 组(0.193± 0.045)明显低于C 组(0.342± 0.007),差异有统计学意义(P＜0.05);A 组、B 组之间比较无明显差异。RT-PCR 检测 RANKL相对量A 组(0.575± 0.143)、B 组(0.543± 0.174)明显低于C 组(0.951± 0.362),差异有统计学意义(P＜0.05);A 组、B 组之 间比较无明显差异。RANK 相对量A 组(0.433± 0.025)、B组(0.611± 0.209)明显低于C 组(0.871± 0.211),差异有统计学意义(P＜ 0.05);A 组、B 组之间比较无明显差异。结论：中药补骨脂对人工关节置换术后假体周围骨溶解,假体无菌性松动具有抑制作用。     

补骨脂抑制人工关节假体周围骨溶解的研究

目的：探讨中药补骨脂对人工关节置换术后假体周围骨溶解,假体无菌性松动的核因子KB受体活化因子配体-核因子KB受体活化因子受体-骨保护素（RANKL-RANK-OPG）信号通路的作用。方法：取24只200＋5g雌性SD大鼠。随机分为A、B、C组,均注射钛颗粒溶液建立骨溶解模型,术后A组采用中药补骨脂水溶液腹腔注射,B组采用外源性OPG腹腔注射作为阳性对照,C组采用生理盐水腹腔注射作为阴性对照。给药4周后,通过免疫组化及反转录聚合酶链反应（RT-PCR）检测各组动物体内RANKL／RANK的表达水平变化。结果：用药4周后,3组12只大鼠背部气囊均为厚壁囊腔,骨溶解模型成功建立,免疫组化及RT-PCR检测RANKIJRANK均呈阳性表达。免疫组化RANKL平均光密度（AOD）值A组（0．168±0．017）、B组（0．147±0．009）明显低于C组（0．314±0．011）,差异有统计学意义（P〈0．05）;A组、B组之间比较无明显差异。RANKAOD值测定A组（0．172±0．015）、B组（0．193±0．045）明显低于C组（0．342±0．007）,差异有统计学意义（P〈0．05）;A组、B组之间比较无明显差异。RT-PCR检测RANKL相对量A组（0．575±0．143）、B组（0．543±0．174）明显低于C组（0．951±0．362）,差异有统计学意义（P〈0．05）;A组、B组之间比较无明显差异。RANK相对量A组（0．433±0．025）、B组（0．611±0．209）明显低于C组（0．871±0．211）,差异有统计学意义（P〈0．05）;A组、B组之间比较无明显差异。结论：中药补骨脂对人工关节置换术后假体周围骨溶解,假体无菌性松动具有抑制作用。     

Finite element analysis of retroacetabular osteolytic defects following total hip replacement

Periprosthetic osteolysis in the retroacetabular region with cancellous bone loss is a recognized phenomenon in the long-term follow-up of total hip replacement. The effects on load transfer in the presence of defects are less well known. A finite element model incorporating a retroacetabular defect behind a cementless component was validated against a 4th generation sawbone pelvis. Computational predictions of surface strain and von Mises stresses were closely correlated to experimental findings. The presence of a cancellous defect increased von Mises stress in the cortical bone of the medial wall of the pelvis. At a load of 600 N this was under the predicted failure stress for cortical bone. Increases in the cup size relative to the acetabulum caused increased stress in the cortical bone of the lateral wall of the pelvis, adjacent to the acetabulum. We are confident that our modeling approach can be applied to patient specific defects to predict pelvis stress with large loads and a range of activities.     

Hedgehog signaling induced by breast cancer cells promotes osteoclastogenesis and osteolysis

Bone integrity is maintained by a dynamic equilibrium between the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. Osteolytic lesions are a painful consequence of metastasis of breast cancer cells to bone in an overwhelming majority of breast cancer patients. Factors secreted by breast cancer cells propel a cascade of events that trigger osteoclastogenesis and elevated bone resorption. In the present study, we show that the Hedgehog (Hh) ligands secreted by breast cancer cells promote osteoclast differentiation and potentiate the activity of mature osteoclasts. Paracrine Hh signaling induced by breast cancer cells mediates a detrimental chain of events by the up-regulation of osteopontin (OPN), which in turn enhances osteoclastic activity by up-regulating cathepsin K and MMP9. Hh signaling is essential for osteoclasts because blocking the Hh pathway using the pharmacological Hh inhibitor, cyclopamine, results in an overall decrease in osteoclastogenesis and resorptive activity. Our studies suggest that inhibiting Hh signaling interferes with the ability of pre-osteoclasts to respond to the stimulatory effects of the breast cancer cells, indicating that Hh signaling is vital to osteoclast activity.