The toothless osteopetrotic rat has a normal vitamin D-binding protein-macrophage activating factor (DBP-MAF) cascade and chondrodysplasia resistant to treatments with colony stimulating factor-1 (CSF-1) and/or DBP-MAF.

The osteopetrotic rat mutation toothless (tl) is characterized by little or no bone resorption, few osteoclasts and macrophages, and chondrodysplasia at the growth plates. Short-term treatment of tl rats with colony-stimulating factor-1 (CSF-1) has been shown to increase the number of osteoclasts and macrophages, producing dramatic resolution of skeletal sclerosis at some, but not all, sites. Defects in production of vitamin D-binding protein-macrophage activating factor (DBP-MAF) have been identified in two other independent osteopetrotic mutations of the rat (op and ia), and two in the mouse (op and mi), in which macrophages and osteoclasts can be activated by the administration of exogenous DBP-MAF. The present studies were undertaken to examine the histology and residual growth defects in tl rats following longer CSF-1 treatments, to investigate the possibility that exogenous DBP-MAF might act synergistically with CSF-1 to improve the tl phenotype, and to assess the integrity of the endogenous DBP-MAF pathway in this mutation. CSF-1 treatment-with or without DBP-MAF-induced resorption of metaphyseal bone to the growth plate on the marrow side, improved slightly but did not normalize long bone growth, and caused no improvement in the abnormal histology of the growth plate. Injections of lysophosphatidylcholine (lyso-Pc) to prime macrophage activation via the DBP-MAF pathway raised superoxide production to similar levels in peritoneal macrophages from both normal and mutant animals, indicating no defect in the DBP-MAF pathway in tl rats. Interestingly, pretreatments with CSF-1 alone also increased superoxide production, although the mechanism for this remains unknown. In summary, we find that, unlike other osteopetrotic mutations investigated to date, the DBP-MAF pathway does not appear to be defective in the tl rat; that additional DBP-MAF does not augment the beneficial skeletal effects seen with CSF-1 alone; and that the growth plate chondrodystrophy seen in this mutation is unaffected by either molecule. Thus, the tl mutation intercepts the function of a gene required for both normal endochondral ossification and bone resorption, thereby uncoupling the coordination of skeletal metabolism required for normal long bone growth.     

A novel immunoassay for the determination of tartrate-resistant acid phosphatase 5b from rat serum.

Osteoclasts secrete tartrate-resistant acid phosphatase 5b (TRACP 5b) into the circulation. We have developed an immunoassay for the determination of rat TRACP 5b activity. Intra-assay variation of the immunoassay was 4.5%, interassay variation was 3.8%, dilution linearity was 104.6 +/- 7.6%, and recovery of recombinant rat TRACP was 99.1 +/- 5.8%. We studied serum TRACP 5b as a marker of bone resorption using orchidectomized (ORC) rats as a model for osteoporosis and age-matched sham-operated rats as controls in a 6-month study. After the operation, trabecular bone mineral density decreased significantly more in the ORC group than in the sham group, whereas cortical bone mineral density increased similarly in both groups. Serum TRACP 5b activity was significantly elevated within the first week after ORC, returned to the control level in the third week, and was not increased above the sham level at any of the later time points. At 6 months, trabecular bone volume was 80% lower in ORC rats than in controls. Osteoclast number per trabecular bone perimeter was slightly increased, but the absolute number of osteoclasts in trabecular bone was significantly decreased. These results suggest that absolute bone resorption is increased within the first week after ORC. Later, it is decreased because there is less bone to be resorbed. However, relative bone resorption (compared with the amount of remaining bone) is still increased, leading to further bone loss. We conclude that serum TRACP 5b is a useful marker for monitoring changes in the bone resorption rate in rat ORC model.     

Tumor‐derived syndecan‐1 mediates distal cross‐talk with bone that enhances osteoclastogenesis

Tumor‐stimulated bone resorption fuels tumor growth and marks a dramatic decline in the health and prognosis of breast cancer patients. Identifying mechanisms that mediate cross‐talk between tumor and bone remains a key challenge. We previously demonstrated that breast cancer cells expressing high levels of heparanase exhibit enhanced shedding of the syndecan‐1 proteoglycan. Moreover, when these heparanase‐high cells are implanted in the mammary fat pad, they elevate bone resorption. In this study, conditioned medium from breast cancer cells expressing high levels of heparanase was shown to significantly stimulate human osteoclastogenesis in vitro (p < .05). The osteoclastogenic activity in the medium of heparanase‐high cells was traced to the presence of syndecan‐1, intact heparan sulfate chains, and heat‐labile factor(s), including the chemokine interleukin 8 (IL‐8). The enhanced osteoclastogenesis promoted by the heparanase‐high cells results in a dramatic increase in bone resorption in vitro. In addition, the long bones of animals bearing heparanase‐high tumors in the mammary fat pad had significantly higher numbers of osteoclasts compared with animals bearing tumors expressing low levels of heparanase (p < .05). Together these data suggest that syndecan‐1 shed by tumor cells exerts biologic effects distal to the primary tumor and that it participates in driving osteoclastogenesis and the resulting bone destruction. © 2010 American Society for Bone and Mineral Research     

Novel Genetic Models of Osteoporosis by Overexpression of Human RANKL in Transgenic Mice

Receptor activator of NF‐κB ligand (RANKL) plays a key role in osteoclast‐induced bone resorption across a range of degenerative bone diseases, and its specific inhibition has been recently approved as a treatment for women with postmenopausal osteoporosis at high or increased risk of fracture in the United States and globally. In the present study, we generated transgenic mice (TghuRANKL) carrying the human RANKL (huRANKL) genomic region and achieved a physiologically relevant pattern of RANKL overexpression in order to establish novel genetic models for assessing skeletal and extraskeletal pathologies associated with excessive RANKL and for testing clinical therapeutic candidates that inhibit human RANKL. TghuRANKL mice of both sexes developed early‐onset bone loss, and the levels of huRANKL expression were correlated with bone resorption and disease severity. Low copy Tg5516 mice expressing huRANKL at low levels displayed a mild osteoporotic phenotype as shown by trabecular bone loss and reduced biomechanical properties. Notably, overexpression of huRANKL, in the medium copy Tg5519 line, resulted in severe early‐onset osteoporosis characterized by lack of trabecular bone, destruction of the growth plate, increased osteoclastogenesis, bone marrow adiposity, increased bone remodeling, and severe cortical bone porosity accompanied by decreased bone strength. An even more severe skeletal phenotype developed in the high copy Tg5520 founder with extensive soft tissue calcification. Model validation was further established by evidence that denosumab, an antibody that inhibits human but not murine RANKL, fully corrected the hyper‐resorptive and osteoporotic phenotypes of Tg5519 mice. Furthermore, overexpression of huRANKL rescued osteopetrotic phenotypes of RANKL‐defective mice. These novel huRANKL transgenic models of osteoporosis represent an important advance for understanding the pathogenesis and treatment of high‐turnover bone diseases and other disease states caused by excessive RANKL. © 2014 American Society for Bone and Mineral Research.     

Promotion of normal healing of bone defects under estrogen deficiency by implantation of beta‐tricalcium phosphate composed of rod‐shaped particles

We compared the healing of bone defects in ovariectomized rats implanted with beta‐tricalcium phosphate (β‐TCP) composed of rod‐shaped particles, which were prepared using the applied hydrothermal method (HTCP), and that of bone defects implanted with conventional β‐TCP composed of globular‐shaped particles (CTCP), which were prepared by normal sintering. Eight‐week‐old female Wistar rats were ovariectomized, and 2 weeks after the operation, 0.5‐ to 0.6‐mm diameter spherical granules of each ceramic were implanted in a bone defect created in the distal end of the femur. Four, 8, and 12 weeks after implantation, the amount of newly formed bone implanted with HTCP was significantly larger than that implanted with CTCP and was equivalent to that in non‐ovariectomized sham‐operated rats. Without implantation, spontaneous repair of the trabecular bone was barely observed. The physiological structure of the trabecular network was maintained in the region implanted with HTCP, but that in the region implanted with CTCP was severely destroyed. Gene expression microarray analysis revealed that the expression of genes involved in interferon signaling pathways was upregulated in osteoclasts cultured on HTCP compared with that cultured on CTCP. Our results suggest that the microstructure of β‐TCP affected the biological behavior of osteoclasts and regulated local bone metabolism. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:189–196, 2014.     

Effects of Odanacatib on the Radius and Tibia of Postmenopausal Women: Improvements in Bone Geometry,Microarchitecture, and Estimated Bone Strength

The cathepsin K inhibitor odanacatib (ODN), currently in phase 3 development for postmenopausal osteoporosis, has a novel mechanism of action that reduces bone resorption while maintaining bone formation. In phase 2 studies, odanacatib increased areal bone mineral density (aBMD) at the lumbar spine and total hip progressively over 5 years. To determine the effects of ODN on cortical and trabecular bone and estimate changes in bone strength, we conducted a randomized, double‐blind, placebo‐controlled trial, using both quantitative computed tomography (QCT) and high‐resolution peripheral (HR‐p)QCT. In previously published results, odanacatib was superior to placebo with respect to increases in trabecular volumetric BMD (vBMD) and estimated compressive strength at the spine, and integral and trabecular vBMD and estimated strength at the hip. Here, we report the results of HR‐pQCT assessment. A total of 214 postmenopausal women (mean age 64.0 ± 6.8 years and baseline lumbar spine T‐score –1.81 ± 0.83) were randomized to oral ODN 50 mg or placebo, weekly for 2 years. With ODN, significant increases from baseline in total vBMD occurred at the distal radius and tibia. Treatment differences from placebo were also significant (3.84% and 2.63% for radius and tibia, respectively). At both sites, significant differences from placebo were also found in trabecular vBMD, cortical vBMD, cortical thickness, cortical area, and strength (failure load) estimated using finite element analysis of HR‐pQCT scans (treatment differences at radius and tibia = 2.64% and 2.66%). At the distal radius, odanacatib significantly improved trabecular thickness and bone volume/total volume (BV/TV) versus placebo. At a more proximal radial site, odanacatib attenuated the increase in cortical porosity found with placebo (treatment difference = –7.7%, p = 0.066). At the distal tibia, odanacatib significantly improved trabecular number, separation, and BV/TV versus placebo. Safety and tolerability were similar between treatment groups. In conclusion, odanacatib increased cortical and trabecular density, cortical thickness, aspects of trabecular microarchitecture, and estimated strength at the distal radius and distal tibia compared with placebo. © 2014 American Society for Bone and Mineral Research     

Effect of vitamin K2 on cortical and cancellous bones in orchidectomized and/or sciatic neurectomized rats.

We examined the effect of vitamin K2 on cortical and cancellous bones in orchidectomized and/or sciatic neurectomized rats. Ninety male Sprague-Dawley rats, 3 months of age, were randomized by stratified weight method into nine groups with 10 rats in each group: baseline control (BLC), age-matched intact control (IN), IN+vitamin K2 administration (K), orchidectomy (ORX), ORX+K, unilateral sciatic neurectomy (NX), NX+K, ORX+NX (ONX), and ONX+K. Vitamin K2 (menatetrenone) was administered orally twice a week at a dose of 30 mg/kg each. After 10 weeks of feeding, the tibial shaft and proximal tibia were processed for cortical and cancellous bone histomorphometric analyses, respectively. An ORX-induced reduction in maturation-related cortical bone gain and ORX-induced cancellous bone loss were attributable to increased endocortical and trabecular bone turnover, respectively. NX- and ONX-induced reductions in maturation-related cortical bone gain were attributable to decreased periosteal bone formation and increased endocortical bone turnover, while NX- and ONX-induced cancellous bone loss was attributable to increased bone resorption and decreased bone formation. ORX-induced cancellous bone loss was more pronounced when combined with immobilization. Vitamin K2 administration did not significantly alter any parameters in IN rats. Vitamin K2 administration in ORX rats suppressed endocortical bone resorption and trabecular bone turnover, retarding a reduction in maturation-related cortical bone gain and cancellous bone loss. This effect on cancellous bone loss was primarily because of prevention of a reduction of trabecular thickness. Vitamin K2 administration in NX and ONX rats suppressed bone resorption and stimulated bone formation (mineralization), with retardation of a reduction of trabecular thickness without any significant effect on cancellous bone mass, and suppressed endocortical bone resorption, retarding a reduction in maturation-related cortical bone gain. The present study provides evidence indicating that vitamin K2 has the potential to suppress bone resorption or bone turnover and/or stimulate bone formation in vivo in ORX and/or NX rats.     

Inflammation-mediated osteopenia (IMO) during acute inflammation in rats is due to a transient inhibition of bone formation

Summary Local inflammation was induced in rats through the subcutaneous injection of magnesium silicate. Trabecular bone volume of the tibia decreased progressively during a 3 week observation period following the inflammatory stimulus. The trabecular bone surface covered with osteoblasts was strikingly reduced during the first week but had normalized by the end of the third week. Calcification rate in the cortical bone of the tibia was reduced with a parallel reduction in endosteal osteoid seam width. Both calcification rate and tetracycline double-labeled surface of vertebral trabecular bone were reduced during the first 2 weeks. Neither total bone resorption surface nor active bone resorption surface were increased. There was a decrease in osteoclast numbers/mm² bone tissue associated with decreasing bone volume. Our data demonstrate a transient inhibition of bone formation during acute inflammation in the rat and indicate that changes in osteoblast function are part of the acute phase response following local inflammation.     

Adaptations in the Microarchitecture and Load Distribution of Maternal Cortical and Trabecular Bone in Response to Multiple Reproductive Cycles in Rats

Pregnancy, lactation, and weaning result in dramatic changes in maternal calcium metabolism. In particular, the increased calcium demand during lactation causes a substantial degree of maternal bone loss. This reproductive bone loss has been suggested to be largely reversible, as multiple clinical studies have found that parity and lactation history have no adverse effect on postmenopausal fracture risk. However, the precise effects of pregnancy, lactation, and post‐weaning recovery on maternal bone structure are not well understood. Our study aimed to address this question by longitudinally tracking changes in trabecular and cortical bone microarchitecture at the proximal tibia in rats throughout three cycles of pregnancy, lactation, and post‐weaning using in vivo μCT. We found that the trabecular thickness underwent a reversible deterioration during pregnancy and lactation, which was fully recovered after weaning, whereas other parameters of trabecular microarchitecture (including trabecular number, spacing, connectivity density, and structure model index) underwent a more permanent deterioration, which recovered minimally. Thus, pregnancy and lactation resulted in both transient and long‐lasting alterations in trabecular microstructure. In the meantime, multiple reproductive cycles appeared to improve the robustness of cortical bone (resulting in an elevated cortical area and polar moment of inertia), as well as increase the proportion of the total load carried by the cortical bone at the proximal tibia. Taken together, changes in the cortical and trabecular compartments suggest that whereas rat tibial trabecular bone appears to be highly involved in maintaining calcium homeostasis during female reproduction, cortical bone adapts to increase its load‐bearing capacity, allowing the overall mechanical function of the tibia to be maintained. © 2017 American Society for Bone and Mineral Research.     

Glucocorticoid-Induced Osteoporosis in Growing Rats

This study evaluated whether growing rats were appropriate animal models of glucocorticoid-induced osteoporosis. The 3-month-old male rats were treated with either vehicle or prednisone acetate at 1.5, 3.0, and 6.0 mg/kg/day by oral gavage, respectively. All rats were injected with tetracycline and calcein before sacrificed for the purpose of double in vivo labeling. Biochemistry, histomorphometry, mechanical test, densitometry, micro-CT, histology, and component analysis were performed. We found that prednisone treatments dose dependently decreased body weight, serum biomarkers, biomechanical markers, bone formation, and bone resorption parameters in both tibial and femoral trabecular bone without trabecular bone loss. We also found that significant bone loss happened in femoral cortical bone in the glucocorticoid-treated rats. The results suggested that prednisone not only inhibited bone formation, but also inhibited bone resorption which resulted in poor bone strength but with no cancellous bone loss in growing rats. These data also suggested that the effects of glucocorticoid on bone metabolism were different between cortical bone and trabecular bone, and different between tibia and femur. Growing rats may be a glucocorticoid-induced osteoporosis animal model when evaluated the effects of drugs upon juvenile patients exposed to GC for a long time.     

Dissociation of angiogenesis and osteoclastogenesis during endochondral bone formation in neonatal mice.

Invasion of the mineralized matrix by endothelial cells and osteoclasts is a key event in endochondral bone formation. To examine the putative role of osteoclast activity in the angiogenic process, we used two in vivo models of suppressed bone resorption: mice treated with the bisphosphonate clodronate and in osteoclast-deficient, osteopetrotic mice. Angiogenesis was assessed in caudal vertebrae of these neonatal mice. This model enables us to study the interaction between osteoclasts and endothelial cells during endochondral bone formation. In control conditions, sinusoid-like structures were detected in the vicinity of tartrate resistance acid phosphatase positive (TRAcP+) osteoclasts. Treatment with clodronate completely abolished osteoclastic bone resorption, whereas angiogenesis remained unaffected. In line with these observations, in the osteopetrotic mouse mutants c-fos knockout mice and op/op mice, capillaries invaded the calcified cartilage in the absence of osteoclasts. In conclusion, our data strongly suggest that during endochondral bone formation, vascular invasion can occur in the absence of osteo(chondro)clastic resorption. In addition, bisphosphonates show no apparent effect on angiogenesis in this in vivo model. These findings may have important clinical implications in the management of skeletal disorders such as metastatic bone disease, in which both osteoclastic bone resorption and angiogenesis contribute to tumor growth. On the other hand, our results confirm that bisphosphonates can be used safely in the treatment of disorders that affect the growing skeleton, such as in juvenile osteoporosis.     

破骨细胞研究新进展

破骨细胞是起源于骨髓单核细胞的多核细胞,成熟的破骨细胞位于骨小梁和骨皮质内表面。骨组织稳态受成骨细胞产生的骨形成和破骨细胞引起的骨吸收之间的平衡调节。然而在病理状态下,多种因素,包括肿瘤坏死因子超家族配体和炎性蛋白质等都促进破骨细胞的形成,使骨代谢失去平衡,导致骨组织过度吸收和过度形成。破骨细胞过度活化常见于骨质疏松症,自身免疫性关节炎等骨代谢疾病。破骨细胞功能障碍同样会导致如石骨症等疾病。因此,破骨细胞是骨代谢疾病预防和治疗方面的重要靶点。随着研究的深入,近年来有关破骨细胞的研究有了新的发现。本文就破骨细胞最新研究进展做一综述。     

Cathepsin K Controls Cortical Bone Formation by Degrading Periostin

Although inhibitors of bone resorption concomitantly reduce bone formation because of the coupling between osteoclasts and osteoblasts, inhibition or deletion of cathepsin k (CatK) stimulates bone formation despite decreasing resorption. The molecular mechanisms responsible for this increase in bone formation, particularly at periosteal surfaces where osteoclasts are relatively poor, remain unclear. Here we show that CatK pharmacological inhibition or deletion (Ctsk^‐/‐ mice) potentiates mechanotransduction signals mediating cortical bone formation. We identify periostin (Postn) as a direct molecular target for degradation by CatK and show that CatK deletion increases Postn and β‐catenin expression in vivo, particularly at the periosteum. In turn, Postn deletion selectively abolishes cortical, but not trabecular, bone formation in CatK‐deficient mice. Taken together, these data indicate that CatK not only plays a major role in bone remodeling but also modulates modeling‐based cortical bone formation by degrading periostin and thereby moderating Wnt‐β‐catenin signaling. These findings provide novel insights into the role of CatK on bone homeostasis and the mechanisms of increased cortical bone volume with CatK mutations and pharmacological inhibitors. © 2017 American Society for Bone and Mineral Research.     

In vivo actions of insulin-like growth factor-I (IGF-I) on bone formation and resorption in rats

The in vivo action of insulin-like growth factor-I on bone metabolism has been studied using a new model. Insulin-like growth factor-I (IGF-I) was continuously infused into the arterial supply of the right hindlimb of ambulatory rats for up to 14 days and the effects on cortical and trabecular bone formation and the number of osteoclasts were determined by histomorphometric techniques. The contralateral limb acted as an internal control. IGF-I infusion significantly increased cortical bone formation (p less than 0.01). Trabecular bone was increased 22% (p = 0.07), but the infusion was only for seven days. These effects of IGF-I were age dependent, being absent in young, rapidly growing animals, but present at least until one year of age. IGF-I appears to be a purely anabolic hormone for bone formation, since it significantly stimulates osteoblasts and decreases the number of osteoclasts. Thus, although IGF-I mediates the growth-promoting effect of growth hormone, it does not mediate growth hormone's action on bone resorption.     

Cortical and Trabecular Bone Benefits of Mechanical Loading Are Maintained Long Term in Mice Independent of Ovariectomy

Skeletal loading enhances cortical and trabecular bone properties. How long these benefits last after loading cessation remains an unresolved, clinically relevant question. This study investigated long‐term maintenance of loading‐induced cortical and trabecular bone benefits in female C57BL/6 mice and the influence of a surgically induced menopause on the maintenance. Sixteen‐week‐old animals had their right tibia extrinsically loaded 3 days/week for 4 weeks using the mouse tibial axial compression loading model. Left tibias were not loaded and served as internal controls. Animals were subsequently detrained (restricted to cage activities) for 0, 4, 8, 26, or 52 weeks, with ovariectomy (OVX) or sham‐OVX surgery being performed at 0 weeks detraining. Loading increased midshaft tibia cortical bone mass, size, and strength, and proximal tibia bone volume fraction. The cortical bone mass, area, and thickness benefits of loading were lost by 26 weeks of detraining because of heightened medullary expansion. However, loading‐induced benefits on bone total area and strength were maintained at each detraining time point. Similarly, the benefits of loading on bone volume fraction persisted at all detraining time points. The long‐term benefits of loading on both cortical and trabecular bone were not influenced by a surgically induced menopause because there were no interactions between loading and surgery. However, OVX had independent effects on cortical bone properties at early (4 and 8 weeks) detraining time points and trabecular bone properties at all detraining time points. These cumulative data indicate loading has long‐term benefits on cortical bone size and strength (but not mass) and trabecular bone morphology, which are not influenced by a surgically induced menopause. This suggests skeletal loading associated with physical activity may provide long‐term benefits by preparing the skeleton to offset both the cortical and trabecular bone changes associated with aging and menopause. © 2014 American Society for Bone and Mineral Research.     

Lymphatic Endothelial Cells Produce M‐CSF,Causing Massive Bone Loss in Mice

Gorham‐Stout disease (GSD) is a rare bone disorder characterized by aggressive osteolysis associated with lymphatic vessel invasion within bone marrow cavities. The etiology of GSD is not known, and there is no effective therapy or animal model for the disease. Here, we investigated if lymphatic endothelial cells (LECs) affect osteoclasts (OCs) to cause a GSD osteolytic phenotype in mice. We examined the effect of a mouse LEC line on osteoclastogenesis in co‐cultures. LECs significantly increased receptor activator of NF‐κB ligand (RANKL)‐mediated OC formation and bone resorption. LECs expressed high levels of macrophage colony‐stimulating factor (M‐CSF), but not RANKL, interleukin‐6 (IL‐6), and tumor necrosis factor (TNF). LEC‐mediated OC formation and bone resorption were blocked by an M‐CSF neutralizing antibody or Ki20227, an inhibitor of the M‐CSF receptor, c‐Fms. We injected LECs into the tibias of wild‐type (WT) mice and observed massive osteolysis on X‐ray and micro‐CT scans. Histology showed that LEC‐injected tibias had significant trabecular and cortical bone loss and increased OC numbers. M‐CSF protein levels were significantly higher in serum and bone marrow plasma of mice given intra‐tibial LEC injections. Immunofluorescence staining showed extensive replacement of bone and marrow by podoplanin+ LECs. Treatment of LEC‐injected mice with Ki20227 significantly decreased tibial bone destruction. In addition, lymphatic vessels in a GSD bone sample were stained positively for M‐CSF. Thus, LECs cause bone destruction in vivo in mice by secreting M‐CSF, which promotes OC formation and activation. Blocking M‐CSF signaling may represent a new therapeutic approach for treatment of patients with GSD. Furthermore, tibial injection of LECs is a useful mouse model to study GSD. © 2017 American Society for Bone and Mineral Research.     

Review of cellular mechanisms of tumor osteolysis

The cellular and biochemical mechanisms that direct the destruction of bone at sites of tumor osteolysis are unknown. To better understand the mechanisms through which tumors direct bone resorption, research has focused on developing in vivo and in vitro experimental models that are useful for studying this process. In vivo experimental systems have been developed that permit study of tumor osteolysis from human and murine tumors, and that permit the study of tumors that arise from (sarcoma) or can metastasize (breast cancer) to bone. Recent research has focused on three questions: (1) Are osteoclasts or tumor cells responsible for bone resorption during tumor osteolysis? (2) What are the cellular mechanisms that are responsible for bone resorption during tumor osteolysis, and (3) what are the tumor cell products that regulate the cellular mechanisms that are responsible for tumor osteolysis? It has been determined that osteoclasts are responsible for bone resorption at sites of tumor osteolysis by enhancing the binding of osteoclast to bone, by inducing osteoclastic bone resorption, and by stimulating osteoclast formation. Attempts to identify tumor cell products that regulate these cellular mechanisms are in progress, and findings suggest that production of macrophage colony stimulating factor may be required for tumor osteolysis to occur with some tumors.     

Supplementation with Green Tea Polyphenols Improves Bone Microstructure and Quality in Aged,Orchidectomized Rats

Recent studies show that green tea polyphenols (GTPs) attenuate bone loss and microstructure deterioration in ovariectomized aged female rats, a model of postmenopausal osteoporosis. This study evaluated the efficacy of GTPs at mitigating bone loss and microstructure deterioration along with related mechanisms in androgen-deficient aged rats, a model of male osteoporosis. A 2 (sham vs. orchidectomy) × 2 (no GTP and 0.5% GTP in drinking water) factorial design was studied for 16 weeks using 40 aged male rats. An additional 10 rats (baseline group) were killed at the beginning of study to provide baseline parameters. There was no difference in femoral mineral density between baseline and the sham only group. Orchidectomy suppressed serum testosterone and tartrate-resistant acid phosphatase concentrations, liver glutathione peroxidase activity, bone mineral density, and bone strength. Orchidectomy also decreased trabecular bone volume, number, and thickness in the distal femur and proximal tibia and bone-formation rate in trabecular bone of proximal tibia but increased serum osteocalcin concentrations and bone-formation rates in the endocortical tibial shaft. GTP supplementation resulted in increased serum osteocalcin concentrations, bone mineral density, and trabecular volume, number, and strength of femur; increased trabecular volume and thickness and bone formation in both the proximal tibia and periosteal tibial shaft; decreased eroded surface in the proximal tibia and endocortical tibial shaft; and increased liver glutathione peroxidase activity. We conclude that GTP supplementation attenuates trabecular and cortical bone loss through increasing bone formation while suppressing bone resorption due to its antioxidant capacity.     

Experimental transplantation of the Swarm rat chondrosarcoma into bone: radiological and pathological studies

The Swarm rat chondrosarcoma has been the subject of extensive biochemical studies. However, to our knowledge, there are no previous reports in the literature on transplantation of this tumor into bone. This article describes the natural history of the tumor when implanted into the bone of the rat, and correlates its histological growth pattern with its radiological appearance. Our results showed that the tumor grows slowly in the bone. The rate of intramedullary growth, however, was variable and was not the same in all the animals. Its growth pattern resembles human chondrosarcoma, with extensive invasion of the marrow and cortex. In the first few weeks after implantation, the only radiological changes noted were mild medullary radiopacities. At a later stage, 12-14 weeks postimplantation, as the tumor infiltrated the bone, significant radiological abnormalities were observed in the medullary cavity and cortex. Periosteal reaction was seen after the tumor invaded the cortex with the production of a soft-tissue mass. Distant dissemination was rare; only 1 of 24 rats developed pulmonary metastases. The Swarm rat chondrosarcoma is a well-differentiated malignant tumor that histologically resembles well-differentiated human chondrosarcoma. Transplanted into bone, it may be useful as an experimental model for comparative studies with human chondrosarcoma.     

The effects of tamoxifen on the osteopenia induced by sciatic neurotomy in the rat: A histomorphometric study

Summary The effects of a 3-week treatment with the nonsteroidal “antiestrogen” tamoxifen were determined on cortical and trabecular bone mass of the tibiae of growing male rats that had undergone unilateral sciatic neurotomy (USN). USN resulted in decreases in cortical area (−11.3%), cross-sectional area (−8.4%), and periosteal bone formation rate (−32.6%) in cortical bone, indicating that the disuse osteopenia results in a decrease in bone formation in cortical bone. USN significantly reduced the amount of trabecular bone in our metaphyseal sampling site (−75%), markedly increasing the amount of bone surface lined by osteoclasts (+65%) without affecting the surface lined by osteoblasts. These results suggest that trabecular bone disuse osteopenia is due, at least in part, to increased bone resorption. Tamoxifen treatment significantly reduced the loss of trabecular bone, restoring resorbing surface length to the control (sham-operated) animal levels. Tamoxifen treatment of sham-operated animals increased trabecular bone area and surface by 35.7% (±10.5) and 41.8% (±7.8), respectively, and reduced resorbing surface by 21.5% (±11.6) compared with sham-operated placebo-treated rats. Tamoxifen had no significant effect on cortical bone parameters in the sham-operated group. The results indicate that tamoxifen is able to reduce the trabecular bone loss that results from USN, but has no effect on cortical bone disuse osteopenia, or on trabecular bone formation. Moreover, tamoxifen treatment of control (intact) animals inhibited the normal levels of bone resorption occurring in these rapidly growing animals.