Anabolic action of parathyroid hormone regulated by the β2-adrenergic receptor

Parathyroid hormone (PTH), the major calcium-regulating hormone, and norepinephrine (NE), the principal neurotransmitter of sympathetic nerves, regulate bone remodeling by activating distinct cell-surface G protein-coupled receptors in osteoblasts: the parathyroid hormone type 1 receptor (PTHR) and the β(2)-adrenergic receptor (β(2)AR), respectively. These receptors activate a common cAMP/PKA signal transduction pathway mediated through the stimulatory heterotrimeric G protein. Activation of β(2)AR via the sympathetic nervous system decreases bone formation and increases bone resorption. Conversely, daily injection of PTH (1-34), a regimen known as intermittent (i)PTH treatment, increases bone mass through the stimulation of trabecular and cortical bone formation and decreases fracture incidences in severe cases of osteoporosis. Here, we show that iPTH has no osteoanabolic activity in mice lacking the β(2)AR. β(2)AR deficiency suppressed both iPTH-induced increase in bone formation and resorption. We showed that the lack of β(2)AR blocks expression of iPTH-target genes involved in bone formation and resorption that are regulated by the cAMP/PKA pathway. These data implicate an unexpected functional interaction between PTHR and β(2)AR, two G protein-coupled receptors from distinct families, which control bone formation and PTH anabolism.     

Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption.

We studied bone biopsies from 26 patients with myelomatosis with apparently normal skeletal metabolism. Quantitative histomorphometric measurements suggested that skeletal disease was progressive despite normocalcaemia and normal urinary excretion rates of calcium and hydroxyproline. When biopsies were divided according to the involvement of marrow by plasma cells, bone resorption--as judged by the eroded surface--increased significantly the greater plasma cell burden. Osteoclasts were frequent with moderate tumour burdens, but there was no further increase in the number of osteoclasts when plasma cell infiltration increased by more than 50% of bone marrow. Contrary to expectation, the numbers of osteoblasts and bone formation rates were increased with bone biopsies with moderate tumour burden, but were markedly lower when plasma cell infiltration occupied more than 50% of bone marrow, due to a decreased functional capacity of osteoblasts. We conclude that skeletal bone disease in myeloma is commonly progressive despite apparently stable bone disease as judged by biochemical measurements. The major mechanism of bone loss in myelomatosis is increased osteoclastic resorption but decreased bone formation contributes to bone loss with heavy plasma cell burdens. Urinary excretion of calcium and hydroxyproline provide insensitive indices of bone resorption in myelomatosis.     

不同投氟方式对诱导性骨形成影响的实验研究

本文研究了不同投氟方式(连续、间断摄氟)对大鼠诱导性异位骨形成的影响。组织学及骨形态计量学研究结果显示:间断投予氟化钠(NaF)具有与持续投予 NaF 相同的刺激骨形成的作用,且诱导性骨质的结构为成熟的板层骨。即未观察到持续投氟组所出现的编织骨和类骨质。作者认为氟对骨细胞和骨质结构的影响主要取决于骨中氟积聚的程度。     

Association between disease-modifying antirheumatic drugs and bone turnover biomarkers

Rheumatoid arthritis (RA) has been linked to an increased risk of osteoporosis as well as fractures. Patients diagnosed with RA had a 25% increased risk of osteoporotic fracture, according to a recent population-based cohort study that compared them to people without RA. Several studies have found a correlation between osteoporosis and the presence of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and 6. These cytokines play a crucial part in the process of bone resorption by boosting osteoclast activation and encouraging osteoclast differentiation. Based on the correlation between RA, osteoporosis, and inflammation, it is possible that systemic immunosuppression with disease-modifying antirheumatic drugs (DMARDs) can help individuals with RA have a lower chance of developing osteoporosis and osteoporotic fractures. There is little information on how different DMARDs, biologic or non-biologic, affect RA patients' bone metabolism. In this study, we present an overview of the influence that targeted therapies, such as biologics, non-biologics, and small molecule inhibitors, have on bone homeostasis in RA patients.     

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人的一生不断进行着骨的新陈代谢。这是通过旧骨吸收和新骨形成来完成。在正常人两者紧密偶联,假如两者失偶联会引起骨量、骨结构和骨强度的改变。但体内骨结构和骨强度很难被检测。近代通过测定骨转换生化标志物了解是否存在骨代谢的失衡。文章介绍骨形成和骨吸收的生化标志物及其临床应用,由于无创伤,价较廉,正被推广应用。     

Dissociation of specific binding of 25-OH-D3 and resorption in fetal rat bones.

Specific binding of 25-OH-D 3 was measured in cytosol prepared from isolated fetal rat bone cells. Binding was significant after 2 h incubation at 0 degrees C and appeared to be approaching a plateau at 4 h. Binding was half-maximal at 1.7 X 10(-10) M 25-OH-D3. 24(R),25-(OH)2D3, which was approximately equipotent with 25-OH-D3 in bone culture, had approximately the same binding activity. 1,25-(OH)2D3, which was 2--3 orders of magnitude more active on resorption, was a much weaker competitor for binding. Vitamin D3, which was inactive in culture, was at least as effective a competitor as 1,25-(OH)2D3. The results suggest that the cytosol site which specifically bind 25-OH-D3 is not the mediator of the bone-resorbing activity.     

A New Anorganic Equine Bone Substitute for Oral Surgery: Structural Characterization and Regenerative Potential

Different xenogeneic inorganic bone substitutes are currently used as bone grafting materials in oral and maxillo-facial surgery. The aim of the present study was to determine the physicochemical properties and the in vivo performance of an anorganic equine bone (AEB) substitute. AEB is manufactured by applying a process involving heating at >300 °C with the aim of removing all the antigens and the organic components. AEB was structurally characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray fluorescence (XRF), and Fourier-transformed infrared (FT-IR) spectroscopy and compared to the anorganic bovine bone (ABB). In order to provide a preliminary evaluation of the in vivo performance of AEB, 18 bone defects were prepared and grafted with AEB (nine sites), or ABB (nine sites) used as a control, in nine Yucatan Minipigs. De novo bone formation, residual bone substitute, as well as local inflammatory and tissue effects were histologically evaluated at 30 and 90 days after implantation. The structural characterization showed that the surface morphology, particle size, chemical composition, and crystalline structure of AEB were similar to cancellous human bone. The histological examination of AEB showed a comparable pattern of newly formed bone and residual biomaterial to that of ABB. Overall, the structural data and pre-clinical evidence reported in the present study suggests that AEB can be effectively used as bone grafting material in oral surgery procedures.     

枕骨大孔区畸形的诊断,分型及意义

对６１例枕骨大孔区畸形患者进行系统观察,并对其中５１例进行了手术治疗,提出将此病分为代偿期和病发期;发病后根据其临床表现为可分为六型：高颈髓型、小脑型、脑积水型,椎基底动脉型、后组颅神经型和混合型。     

慢性肝病患者髂骨病理变化的观察及意义

对１７例乙肝后肝经和１４例慢性活动性肝炎患者的髂骨病理组织学改变进行了观察,发现肝硬化组骨质疏松的发生率为８２．５３％,肝炎组为３５．７１％,两组比较差异显著。提示随肝脏病变程度加重,其相关骨病的发生率亦之增加。将髂骨病理改变分为三组,为诊断肝性骨病（ＨＢＤ）提供了依据。     

Influence of Xenogeneic and Alloplastic Carriers for Bone Augmentation on Human Unrestricted Somatic Stem Cells

Alloplastic and xenogeneic bone grafting materials are frequently used for bone augmentation. The effect of these materials on precursor cells for bone augmentation is yet to be determined. The aim of this study was to ascertain, in vitro, how augmentation materials influence the growth rates and viability of human unrestricted somatic stem cells. The biocompatibility of two xenogeneic and one alloplastic bone graft was tested using human unrestricted somatic stem cells (USSCs). Proliferation, growth, survival and attachment of unrestricted somatic stem cells were monitored after 24 h, 48 h and 7 days. Furthermore, cell shape and morphology were evaluated by SEM. Scaffolds were assessed for their physical properties by Micro-CT imaging. USSCs showed distinct proliferation on the different carriers. Greatest proliferation was observed on the xenogeneic carriers along with improved viability of the cells. Pore sizes of the scaffolds varied significantly, with the xenogeneic materials providing greater pore sizes than the synthetic inorganic material. Unrestricted somatic stem cells in combination with a bovine collagenous bone block seem to be very compatible. A scaffold’s surface morphology, pore size and bioactive characteristics influence the proliferation, attachment and viability of USSCs.     

骨强度对骨量的影响及在临床上的应用

NIH提出诊断骨质疏松（OP）的必备条件是骨强度下降，健康人中的峰值骨骨强度差异大，明确影响骨强度而非骨质疏松病因的主要因素，并排除这些因素的影响后，有利于提高诊断OP的敏感度和准确度，目前已明确骨大小（骨投影面积和体积）和体重两个主要的影响因素，这两个影响因素标准化BMC后的骨量指标应用效果不同；为了在科研和临床中选择适当的骨量指标，本文对这些指标的几何特征、力学特征、与骨强度的关系和应用效果进行分析。     

An update on markers of bone turnover

Biochemical markers of bone turnover are extremely useful in clinical evaluation of treatment efficacy and as estimators of fracture risk, and an in-depth discussion of the origins, pros and cons of several biological markers is of considerable value.     

Inhibition of matrix-induced bone differentiation by advanced glycation end-products in rats

Summary Glycation of long-lived proteins is an inevitable consequence of aging that is accelerated in patients with diabetes mellitus. Treatment of demineralized bone matrix particles from 35-week-old normal Long-Evans rats with glycolaldehyde, a precursor of advanced glycation end-products, was used to assess the effects of bone-matrix glycation on the process of bone differentiation. Matrix was incubated in phosphate buffered saline alone, phosphate buffered saline containing glycolaldehyde, glycolaldehyde plus the advanced glycation product-inhibitor aminoguanidine, or glycolaldehyde plus the advanced glycation product-inhibitor sodium cyanoborohydride. Glycolaldehyde increased the matrix advanced glycation product content as measured by specific fluorescence more than two-fold, while inhibiting bone differentiation more than 90 % as measured by in vivo ⁴⁵CaCl₂ uptake, alkaline phosphatase levels, and histology. In contrast, simultaneous incubation with the advanced glycation product-inhibitor aminoguanidine or sodium cyanoborohydride not only reduced fluorescence to normal, but also restored bone differentiation. Furthermore, the inhibition of bone differentiation by glycolaldehyde was not reversed by subsequent application of recombinant bone morphogenetic protein-2. These observations suggest that formation of advanced glycation products on bone matrix alters its ability to induce bone formation, and probably involves alterations of binding sites for extractable proteins with direct bone inductive properties such as bone morphogenetic protein-2. Decreased bone formation associated with aging and diabetes may result, in part, from advanced glycation product formation on matrix proteins.     

Isolation of malignant cells from human bone marrow using a discontinuous Percoll gradient

A technique for examining relatively large volumes of bone marrow for involvement by malignancy is described. The use of discontinuous Percoll gradients offers no advantage over conventional methods in the diagnosis of hematological malignancy. Its usefulness in detecting infiltration by solid tumor is uncertain. Complete exclusion of malignancy from the fraction containing hematologic stem cells in three patients raises the possibility that this technique is a useful adjunct to other methods of marrow purging before autologous marrow rescue in malignant disease.     

Bone lesions in elderly patients with multiple myeloma: a multicenter study by the Society for Geriatric Hematology

Background: Bone lesions in multiple myeloma (MM) have a significant impact on the quality of life of elderly patients, but they have not been extensively investigated in the elderly. Methods: The subjects were 146 elderly MM patients (aged ≥ 65 years, median age 74) admitted to 11 institutions. Bone lesions were compared with those in 65 non‐elderly MM patients. Results: At the time of diagnosis, skeletal symptoms were present in 104 cases and bone pain in 75. Mixed type occurred more often in elderly patients (63.5%) than in controls (28.3%) (P < 0.0001). Lumbar vertebral lesions were more common in elderly than non‐elderly patients (P < 0.0001). Bone lesions restricted physical activity in 71 elderly patients (48.6%). There was a significant difference between elderly patients with and without bone lesions in the rate of detection of plasma cells in bone marrow. Significant differences were detected in serum calcium concentration, the rate of detection of plasma cells in bone marrow, and serum β2‐microglobulin concentration between patients with and without bone pain, and between those with and without fractures. No significant differences were detected in survival time between elderly patients with and without bone lesions, with and without bone pain, or with and without fractures, whereas a significant difference was seen between these subgroups of non‐elderly patients. Conclusion: Although there were no significant differences in the incidence of bone lesions between elderly and non‐elderly patients, the mixed type of bone lesions occurred more often in the elderly than in controls. Lumbar vertebral lesions were more common in elderly than non‐elderly patients. There was no significant difference in prognosis between elderly patients with and those without bone lesions so the treatment strategy for bone lesions in the elderly should be aimed at improving quality of life through direct treatment of the bone lesions, with subsequent improvement of the related symptoms.     

非经典Wnt信号在骨稳态中的作用

Wnt信号通路是由经典及非经典两类通路组成的一个复杂的蛋白网络,其在骨代谢疾病和肿瘤疾病等研究中至关重要.对于骨代谢疾病早期报道多集中于经典信号通路,但随着研究的不断深入,非经典Wnt信号通路在调控骨稳态(骨形成和骨吸收)中的作用日益受到关注.本文对非经典Wnt配体及其在骨稳态中的作用进行阐述,了解非经典Wnt信号的靶向调控为治疗骨质疏松症等骨稳态失衡相关疾病提供潜在研究方法及新的靶点.     

The dynamics of adult haematopoiesis in the bone and bone marrow environment

This review explores the dynamic relationship between bone and bone marrow in the genesis and regulation of adult haematopoiesis and will provide an overview of the haematopoietic hierarchical system. This will include the haematopoietic stem cell (HSC) and its niches, as well as discuss emerging evidence of the reciprocal interplay between bone and bone marrow, and support of the pleiotropic role played by bone cells in the regulation of HSC proliferation, differentiation and function. In addition, this review will present demineralized bone matrix as a unique acellular matrix platform that permits the generation of ectopic de novo bone and bone marrow and provides a means of investigating the temporal sequence of bone and bone marrow regeneration. It is anticipated that the utilization of this matrix‐based approach will help researchers in gaining deeper insights into the major events leading to adult haematopoiesis in the bone marrow. Furthermore, this model may potentially offer new avenues to manipulate the HSC niche and hence influence the functional output of the haematopoietic system.     

Bone lesions in primary amyloidosis

Amyloidosis primarily involving bone is described in a 59-year-old male pateint. Well circumscribed lytic lesions of the skeleton raised the possibility of myelomatosis. The prolonged insidious course of the disease was uncomplicated by hypercalcemia, pathological fracture, or hematologic abnormalities. The clinical course, together with histological findings and strongly positive bone scan, were the distinguishing features. The osseous manifestations without plasma cell tumor appears to be a rare occurrence in amyloidosis.     

The bone marrow aspirate of healthy subjects

Bone marrow aspirates were obtained from the right or left posterior superior iliac spine of 50 healthy volunteers, 30 men and 20 women. Reference ranges were derived for each cell type and for the myeloid : erythroid (M : E) ratio. The M : E ratio and the percentage of neutrophils were significantly higher in the women and the erythroid component significantly lower. All 28 evaluable men and 11/17 evaluable women had storage iron present in more than trace amounts. The percentage of erythroblasts with detectable iron granules varied very widely, from 3% to 69% in those with more than a trace of storage iron. Minor dyserythropoietic features were present in a high percentage of subjects and 19/50 subjects had one or two dysplastic megakaryocytes. Granulocytic dysplasia was not detected.