Osteoprotegerin and Osteoprotegerin-Ligand Balance: a New Paradigm in Bone Metabolism Providing New Therapeutic Targets

Osteoprotegerin-ligand, also called Osteoclast Differentiation Factor or RANK-ligand, its receptor RANK and its decoy receptor Osteoprotegerin are key molecules regulating osteoclast differentiation and activation. In this view we discuss structure and expression of these molecules, the genetic models addressing their function and their role in in vivo models of osteoclast differentiation and activation. The new paradigm that has evolved from these studies, is not only important in normal bone homeostasis but also appears to play a role in different diseases that affect the skeleton, such as osteoporosis, inflammatory joint disease and cancer. It has opened a new era in bone research by increasing our molecular knowledge and providing new therapeutic targets in bone disease. 5 November 2000 / Accepted: 15 December 2000     

The incisal edge bracket for gold chain attachment to unerupted teeth.

Abstract

A method is described to reduce the morbidity involved in direct bonding of unerupted incisors by use of a precontoured bracket. Increased bracket stability during placement is an additional advantage.     

Integrins,insulin like growth factors,and the skeletal response to load

Bone loss during skeletal unloading, whether due to neurotrauma resulting in paralysis or prolonged immobilization due to a variety of medical illnesses, accelerates bone loss. In this review the evidence that skeletal unloading leads to bone loss, at least in part, due to disrupted insulin like growth factor (IGF) signaling, resulting in reduced osteoblast proliferation and differentiation, will be examined. The mechanism underlying this disruption in IGF signaling appears to involve integrins, the expression of which is reduced during skeletal unloading. Integrins play an important, albeit not well defined, role in facilitating signaling not only by IGF but also by other growth factors. However, the interaction between selected integrins such as αυβ3 and β1 integrins and the IGF receptor are of especial importance with respect to the ability of bone to respond to mechanical load. Disruption of this interaction blocks IGF signaling and results in bone loss. The skeletal response to mechanical load is critical for maintenance of skeletal integrity. This review will assess the interacting roles that insulin like growth factor I (IGF-I) signaling and selected integrins play in this response. Skeletal unloading results in decreased integrin expression, resistance to the anabolic actions of IGF-I, and bone loss.     

Augmentation of TNF-induced osteoclast differentiation by inhibition of ERK and activation of p38: Similar intracellular signaling between RANKL- and TNF-induced osteoclast differentiation

Research in osteoclast differentiation has been greatly advanced since the identification of receptor activator of nuclear factor-κB ligand (RANKL) as osteoclast differentiation factor. The mechanisms of RANKL-induced osteoclast differentiation have been extensively investigated. Mitogen-activated protein kinases (MAPKs) were shown to play crucial roles in RANKL-induced osteoclast differentiation. RANKL-induced osteoclast differentiation was enhanced by inhibition of extracellular signal-regulated kinase (ERK), whereas it was suppressed by inhibition of p38 MAPK. It was reported that tumor necrosis factor (TNF), a major proinflammatory cytokine, induced osteoclast differentiation independently of RANKL. A report showed that inhibition of p38 suppressed TNF-induced osteoclast differentiation, whereas inhibition of ERK did not augment TNF-induced osteoclast differentiation. In this study we reevaluated the roles for MAPKs in TNF-induced osteoclast differentiation. In contrast with the previous report, pretreatment of mouse monocytic RAW264 cells with MAPK/ERK kinase (MEK) inhibitors including PD98059 and U-0126 augmented TNF-induced osteoclast differentiation. Furthermore, we found that U-0126 was more effective in augmentation of osteoclast differentiation than PD98059. Western blot analysis showed that U-0126 inhibited ERK phosphorylation and enhanced p38 phosphorylation, whereas PD98059 inhibited both ERK and p38 phosphorylation. SB203580, a p38 inhibitor, suppressed TNF-induced osteoclast differentiation, and inhibited p38 phosphorylation whereas it augmented ERK phosphorylation. These results demonstrate that ERK inhibition and p38 activation play crucial roles in both RANKL- and TNF-induced osteoclast differentiation.     

Undifferentiated carcinoma of the renal pelvis with osteoclast‐like giant cells: a report of two cases

McCash SI, Unger P, Dillon R, Xiao G‐Q. Undifferentiated carcinoma of the renal pelvis with osteoclast‐like giant cells: a report of two cases. APMIS 2010; 118: 407–12. Undifferentiated carcinoma with osteoclast‐like giant cells arising in the urothelium of the bladder or upper urinary tract is an extremely rare entity. The majority of cases found in the renal pelvis and bladder are associated with either an in situ urothelial malignancy or a conventional high‐grade urothelial carcinoma. These malignancies tend to behave poorly with a grim prognosis and course. We report two additional cases of undifferentiated carcinoma with osteoclast‐like giant cells of the renal pelvis in two patients disease free 42 and 18 months after surgical treatment, respectively.     

Expression of bone sialoprotein (BSP) in developing human tissues

Summary Bone sialoprotein (BSP) and its messenger RNA were localized in developing human skeletal and nonskeletal tissues by means of immunohistochemistry andin situ hybridization. Both protein and mRNA were found in mature, bone-forming cells but not in their immature precursors. In addition, osteoclasts displayed positive immunostaining and high densities of autoradiographic grains byin situ hybridization experiments. BSP was expressed in fetal epiphyseal cartilage cells, particularly in hypertrophic chondrocytes of growth plates. Though neither the protein nor the mRNA were identified in a variety of other connective and nonconnective tissues, an unexpected finding was the expression of BSP in the trophoblast cells of placenta. These findings show that BSP is primarily an osteoblast-derived component of the bone matrix expressed at late stages of differentiation. We have also found that osteoclasts produce BSP, possibly as a mediator of cell attachment to bone.     

Calcitonin gene-related peptide inhibits osteoclastic bone resorption: A comparative study

Summary Besides the calcitonin (CT) precursor, the calcitonin gene also encodes another peptide—calcitonin gene-related peptide (CGRP). We have previously reported that CGRP lowers plasma calcium in the rat. In the present study we have evaluated the effect of CGRP on resorption of bone by isolated rat osteoclasts and have compared these effects to those produced by calcitonins from three species (salmon, pig, and human calcitonins). There was a significant inhibition of bone resorption with rat calcitonin gene-related peptide (rCGRP) at a 1000-fold higher dose than that used for human CT. This effect well explains the CT-like effect of CGRP seen in thein vivo rat CT bioassay. Our results suggest that though CGRP may not be involved in the hormonal control of plasma calcium, the peptide may be an important local regulator of bone cell function.     

Humoral and ionic regulation of osteoclast acidity

Summary Regulation of the acidity of osteoclasts was determinedin situ on the endocranial surfaces of mouse calvaria using acridine orange, a fluorescent weak base. Osteoclasts could be identified by (1) large size, (2) multiple nuclei, (3) relatively small numbers of cells, and (4) the way and the extent to which they took up the dye. Nonosteoclastic cells were stained mainly in their nuclei and occasionally in a few lysosomes surrounding their nuclei, which were uniformly single in nonosteoclasts. Nuclei in osteoclasts were also stained, but the staining of the nuclei was partially masked by the intensity and completeness of the staining of the cytoplasm. In some cells the cytoplasmic staining appeared to be in discrete granules, giving the cytoplasm a bright, frothy appearance. This fluorescence was present in both treated and untreated cells and aided in identifying the osteoclasts. Acridine orange fluorescence at 624 nm intensity, and hence, osteoclast acidity, was increased by parathyroid hormone and prostaglandin E₂. Parathyroid hormone-induced increases in acidity were inhibited by calcitonin, cortisol, sodium fluoride, and prostaglandin E₂. Furthermore, osteoclast acidity was dependent largely or partially on (1) maintenance of K⁺ and Na⁺ gradients, (2) patent Na⁺ channels, (3) chloride-bicarbonate exchange, and (4) H⁺, K⁺-ATPase. These findings demonstrate that osteoclasts become acidified by mechanisms similar to those occurring in gastric parietal cells.     

Mechanisms of promoting the differentiation and bone resorption function of osteoclasts by Staphylococcus aureus infection

Bone infection is a common and serious complication in the field of orthopedics, which frequently leads to excessive bone destruction and fracture nonunion. Staphylococcus aureus (S. aureus) infection affects bone cell function which, in turn, causes bone destruction. Bone is mainly regulated by osteoblasts and osteoclasts. Osteoclasts are the only cell type with bone resorptive function. Their over-activation is closely associated with excessive bone loss. Understanding how S. aureus changes the functional state of osteoclasts is the key to effective treatment. By reviewing the literature, this paper summarizes several mechanisms of bone destruction caused by S. aureus influencing osteoclasts, thereby stimulating new ideas for the treatment of bone infection.     

雌激素治疗骨质疏松大鼠正畸牙周组织中破骨细胞的改变

目的 探讨雌激素对骨质疏松患者正畸牙齿牙周组织中破骨细胞数目，形态的改变。方法 选用30只雌性SD大鼠随机分为三组，正常对照组，骨质疏松组和骨质疏松雌激治疗组。安装矫治器后30d和60d，计数大鼠上颌第一磨牙近中根牙周组织中压力侧破骨细胞数目并进行组织学观察和比较。结果 治疗1月后，破骨细胞数目在骨质疏松组较正常对照组增加64．4％，在雌激素治疗组增加32．9％。治疗2月后，分别增加68．7％和15％。组织学和超微结构观察显示破骨细胞活性骨质疏松组织较正常对照组明显增强，雌激素治疗2月后其活性得到明显抑制。结论 雌激素抑制破骨细胞活性，减少骨吸收。