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PubMed1990

The early effects of aluminium deposition and dialysis on bone in chronic renal failure: a cross-sectional bone-histomorphometric study.

Renal osteodystrophy and aluminium deposition in bone were studied in 19 predialysis and 65 short-term dialysis patients at kidney transplantation during a 1-year period by means of histomorphometric analysis of bone biopsies. All but three patients on dialysis had histological bone disease at transplantation. Hyperparathyroidism was more pronounced in predialysis patients, while the prevalence of stainable bone aluminium (aluminium-positive bone) was greater in dialysis patients (77% versus 37%; P less than 0.05). Aluminium even accumulated in bone with high turnover, while extensive aluminium deposition was associated with delayed mineralisation, hyperosteoidosis, and less fibrosis. Aluminium-stained bone surface was correlated with intake of phosphate binders in non-dialysed patients and with dialysis duration in dialysed patients. All patients dialysed for more than 17 months had aluminium-positive bone. Dialysis patients with aluminium-positive bone had less bone volume and were older than those with aluminium-negative bone. Four patients, all with aluminium-stained bone surface greater than 45% and a dialysis duration exceeding 2 years, had symptomatic bone disease. Our policy of early kidney transplantation may have prevented manifest aluminium-related bone disease in a number of other patients.

Adolescent↗
PubMed2004

Optimization of bone tissue engineering in goats: a peroperative seeding method using cryopreserved cells and localized bone formation in calcium phosphate scaffolds.

BACKGROUND: Bone tissue engineering by combining cultured bone marrow stromal cells with a porous scaffold is a promising alternative for the autologous bone graft. Drawbacks of the technique include the delay necessary for cell culture and the complicated logistics. We investigated methods to bypass these drawbacks. Furthermore, we investigated the localization of bone formation inside the scaffold. METHODS: Bone marrow stromal cells from seven goats were culture expanded and cryopreserved. One week before surgery, some of the cells were thawed, cultured, and seeded on porous calcium phosphate scaffolds. The constructs were cultured for another week until implantation. The remaining cryopreserved cells were thawed just before implantation and peroperatively resuspended in plasma before combining with the scaffold. Scaffolds impregnated with fresh bone marrow, devitalized cultured constructs, and empty scaffolds served as controls. All samples were implanted in the back muscles of the goats for 9 weeks. RESULTS: Histologic examination showed minimal (<1%) bone in the empty and devitalized scaffolds, 4.2 +/- 5.1 bone area percent in the bone marrow samples, and significantly more bone in both the cultured and peroperatively seeded constructs (11.7 +/- 2.5 and 14.0 +/- 2.0%). The peripheral 350 microm of the implants contained significantly less bone. CONCLUSION: Peroperative preparation of osteogenic constructs with cryopreserved cells is feasible. These constructs yield substantially more bone than the scaffolds alone or scaffolds impregnated with fresh bone marrow. Bone deposition is much less on the scaffold periphery.

Animals↗
PubMed2004

Regulation of bone mass and bone turnover by neuronal nitric oxide synthase.

Nitric oxide (NO) is produced by NO synthase (NOS) and plays an important role in the regulation of bone cell function. The endothelial NOS isoform is essential for normal osteoblast function, whereas the inducible NOS isoform acts as a mediator of cytokine effects in bone. The role of the neuronal isoform of NOS (nNOS) in bone has been studied little thus far. Therefore, we investigated the role of nNOS in bone metabolism by studying mice with targeted inactivation of the nNOS gene. Bone mineral density (BMD) was significantly higher in nNOS knockout (KO) mice compared with wild-type controls, particularly the trabecular BMD (P < 0.01). The difference in BMD between nNOS KO and control mice was confirmed by histomorphometric analysis, which showed a 67% increase in trabecular bone volume in nNOS KO mice when compared with controls (P < 0.001). This was accompanied by reduced bone remodeling, with a significant reduction in osteoblast numbers and bone formation surfaces and a reduction in osteoclast numbers and bone resorption surfaces. Osteoblasts from nNOS KO mice, however, showed increased levels of alkaline phosphatase and no defects in proliferation or bone nodule formation in vitro, whereas osteoclastogenesis was increased in nNOS KO bone marrow cultures. These studies indicate that nNOS plays a hitherto unrecognized but important physiological role as a stimulator of bone turnover. The low level of nNOS expression in bone and the in vitro behavior of nNOS KO bone cells indicate that these actions are indirect and possibly mediated by a neurogenic relay.

Animals↗
PubMed2006

Normal bone density obtained in the absence of insulin receptor expression in bone.

Type I diabetes is characterized by little or no insulin production and hyperglycemic conditions. It is also associated with significant bone loss and increased bone marrow adiposity. To examine the role of reduced insulin signaling in type I diabetic bone loss without inducing hyperglycemia, we used genetically reconstituted insulin receptor knockout mice (IRKO-L1) that are euglycemic as a result of human insulin receptor transgene expression in the pancreas, liver, and brain. RT-PCR analyses demonstrated undetectable levels of insulin receptor expression in IRKO-L1 bone, yet IRKO-L1 bones exhibit similar (and trend toward greater) bone density compared with wild-type animals as determined by microcomputed tomography. More detailed bone analyses indicated that cortical bone area was increased in tibias of IRKO-L1 mice. Osteoblast markers (osteocalcin and runx2 mRNA levels) and resorption markers (serum pyridinoline levels) were similar in wild-type and IRKO-L1 bones. When marrow adiposity was examined, we noticed a decrease in adipocyte number and fatty-acid-binding protein 2 expression in IRKO-L1 mice compared with wild-type mice. Bone marrow stromal cell cultures obtained from wild-type and IRKO-L1 mice demonstrated similar adipogenic and osteogenic potentials, indicating that systemic factors likely contribute to differences in marrow adiposity in vivo. Interestingly, IGF-I receptor mRNA levels were elevated in IRKO-L1 bones, suggesting (in combination with hyperinsulinemic conditions) that increased IGF-I receptor signaling may represent a compensatory response and contribute to the changes in cortical bone. Taken together, these results suggest that reduced insulin receptor signaling in bone is not a major factor contributing to bone loss in type I diabetes.

Adipocytes, White↗
PubMed2001

Lasofoxifene (CP-336,156) protects against the age-related changes in bone mass, bone strength, and total serum cholesterol in intact aged male rats.

The purpose of this study was to evaluate if long-term (6 months) treatment with lasofoxifene (LAS), a new selective estrogen receptor modulator (SERM), can protect against age-related changes in bone mass and bone strength in intact aged male rats. Sprague-Dawley male rats at 15 months of age were treated (daily oral gavage) with either vehicle (n = 12) or LAS at 0.01 mg/kg per day (n = 12) or 0.1 mg/kg per day (n = 11) for 6 months. A group of 15 rats was necropsied at 15 months of age and served as basal controls. No significant change was found in body weight between basal and vehicle controls. However, an age-related increase in fat body mass (+42%) and decrease in lean body mass (-8.5%) was observed in controls. Compared with vehicle controls, LAS at both doses significantly decreased body weight and fat body mass but did not affect lean body mass. No significant difference was found in prostate wet weight among all groups. Total serum cholesterol was significantly decreased in all LAS-treated rats compared with both the basal and the vehicle controls. Both doses of LAS treatment completely prevented the age-related increase in serum osteocalcin. Peripheral quantitative computerized tomography (pQCT) analysis at the distal femoral metaphysis indicated that the age-related decrease in total density, trabecular density, and cortical thickness was completely prevented by treatment with LAS at 0.01 mg/kg per day or 0.1 mg/kg per day. Histomorphometric analysis of proximal tibial cancellous bone showed an age-related decrease in trabecular bone volume (TBV; -46%), trabecular number (Tb.N), wall thickness (W.Th), mineral apposition rate, and bone formation rate-tissue area referent. Moreover, an age-related increase in trabecular separation (Tb.Sp) and eroded surface was observed. LAS at 0.01 mg/kg per day or 0.1 mg/kg per day completely prevented these age-related changes in bone mass, bone structure, and bone turnover. Similarly, the age-related decrease in TBV and trabecular thickness (Tb.Th) and the age-related increase in osteoclast number (Oc.N) and osteoclast surface (Oc.S) in the third lumbar vertebral cancellous bone were completely prevented by treatment with LAS at both doses. Further, LAS at both doses completely prevented the age-related decrease in ultimate strength (-47%) and stiffness (-37%) of the fifth lumbar vertebral body. These results show that treatment with LAS for 6 months in male rats completely prevents the age-related decreases in bone mass and bone strength by inhibiting the increased bone resorption and bone turnover associated with aging. Further, LAS reduced total serum cholesterol and did not affect the prostate weight in these rats. Our data support the potential use of a SERM for protecting against the age-related changes in bone and serum cholesterol in elderly men.

Adipose Tissue↗
PubMed2000

Vascular endothelial growth pattern of endochondral bone graft in the presence of demineralized intramembranous bone matrix--quantitative analysis.

OBJECTIVE: To determine the timely ingrowth of new blood vessels of composite endochondral (EC) bone and demineralized bone matrix (DBM) prepared from intramembranous (IM) origin (EC-DBM(IM)) and to compare it with EC bone graft alone. DESIGN: Thirty-two rabbits with 32 critical-size (10 x 5 mm), full-thickness bony defects in rabbit parietal bone were divided into two groups: composite EC-DBM(IM) group-implanted with composite autogenous EC bone and DBM(IM); EC bone group-implanted with EC bone alone. Two rabbits from each group were sacrificed-1, 2, 3, 4, 5, 6, 7, and 14 days after grafting. Neovascularization was assessed by immunohistochemical staining with antihuman angiogenesis-related endothelial cell antibodies (EN 7/44). Quantitative analysis of neovascularization, represented by percentage area of positive immunohistochemical staining, was performed on 320 sections of the experimental groups by a computer-assisted image analyzer. RESULTS: Positive immunohistochemical staining was first identified on day 2 post grafting for the composite EC-DBM(IM) group in comparison with day 4 in the EC bone graft group. The composite EC-DBM(IM) bone graft group showed earlier and almost 100% more neovascularization when compared with the EC bone graft group. CONCLUSION: DBM(IM) enhances healing and integration of EC bone graft by enhancing vascularization as well as increasing the amount of new blood vessels formed. In clinical cases in which EC autogenous bone is used to graft a large defect such as in cleft palate and craniofacial surgery, DBM(IM) should allow better integration and healing of the EC bone graft to the host bone.

Animals↗
PubMed1985

Bone formation enhanced by induction. Bone growth in titanium implants in rats.

Bone-inducing materials have been investigated for the purpose of augmenting bone formation in implants made of porous fiber titanium. The bone-inducing materials used were: (1) Bone from the iliac crest of inbred rats (isografts), (2) Antigen-extracted, autolyzed, demineralized bone from outbred rats (AAA bone a.m. Urist), and (3) AAA bone combined with bone marrow from inbred rats. Tubes of fiber titanium were packed with bone-inducing materials and implanted in the back musculature of inbred rats. Bone formation was assessed by labelling with 3H-proline (collagen synthesis) and 47Ca (mineral deposit) and by content of calcium of the harvested implants. Isografts and AAA bone with marrow yielded a substantial amount of new bone. Without the marrow, AAA bone yielded very small amounts of new bone.

Animals↗
PubMedDate not supplied

A histomorphometric study of bone reactions to titanium implants in irradiated bone and the effect of hyperbaric oxygen treatment.

The present study was undertaken to histomorphometrically analyze early peri-implant bone tissue reactions that occur after radiotherapy and to determine whether hyperbaric oxygen therapy (HBO) affects bone tissue at the microscopic level by altering bone morphology. Twelve rabbits received a single dose (15 Gy) of cobalt60 radiation to one hind leg and the other hind leg served as a control. Titanium screws were placed into the femur and tibia directly after irradiation. Six animals received HBO during the first 4 postoperative weeks. After 8 weeks of follow-up, bone specimens containing the screws were prepared for histomorphometry. Bone-metal contact and the amount of bone in the thread areas and in the mirror areas were measured in a blinded manner. Periosteal bone formation and bone remodeling decreased after irradiation; also after HBO treatment. Hyperbaric oxygen therapy improved bone formation in nonirradiated bone and to some extent also in the irradiated bone. Bone maturation was improved in the HBO animals after irradiation. It was concluded that irradiation reduces the capacity for osseointegration of titanium implants. Hyperbaric oxygen treatment may improve bone formation and especially has positive effects on bone maturation after irradiation.

Animals↗
PubMed2000

[Bone hyperresorption in bone metastases].

MECHANISMS OF BONE LOSS: In patients with bone metastases, bone loss is the consequence of a dissociated process combining excessive bone resorption and inhibited bone formation. This destructive process occurs in response to soluble factors secreted by metastatic cells (PTH-rP, cytokines) which activate osteoclasts. These cells also secrete proteases (cathepsin K, metalloprotease MMP-9) which degrade the bone's collagen network. Excessive bone resorption is also favored by direct interaction between the metastatic cells and stromal cells in the bone marrow in response to the activation of membrane receptors (integrins a4 beta 1 and a4 beta 7). Finally, metastatic cells secrete non-identified soluble factors capable of inhibiting osteoblast proliferation in vitro. EFFECT OF BONE LOSS ON THE METASTASIS: Bone is a major reservoir of growth factors (mainly TGF beta and IGF-1). Positive feedback mechanism operates at the site of osteolysis where TGF beta released by bone tissue induces a paracrine stimulation of PTH-rP production by metastatic cells. IGF-1 released by the bone favors grow of metastatic cells present in the marrow. In addition, IGF-1 as well as collagen proteolytic fragments may stimulate recruitment of new metastatic cells at the site of the bone metastasis. This creates a vicious circle of mutual stimulation between bone destruction and tumor proliferation.

Animals↗
PubMed2002

Bone marrow and bone: a functional unit.

Bone and bone marrow, although often regarded as separate systems, function as a single unit. Cells in the bone marrow are the precursors of bone remodelling cells and exert an important regulatory role both on their own development and the remodelling process, acting as mediators for the effects of systemic and local factors. Other cells, such as immune cells and megakaryocytes, also contribute to the regulation of bone cell development and activity. Many diseases that affect the bone marrow have profound effects on bone, involving interactions between abnormal and normal marrow cells and those of bone. Although recent advances in bone physiology have produced new insights into the relationship between bone marrow and bone cells, much remains to be learnt about the mechanisms by which marrow and bone act in synergy to regulate bone remodelling, both in health and disease.

Aging↗
PubMed1999

Age-related changes in the biochemical properties of human cancellous bone collagen: relationship to bone strength.

The metabolism of bone collagen has received little attention in relation to age-related loss of bone mass and strength. The aim of the present study was to analyze bone collagen content and metabolism in human bone with respect to age. The material consisted of iliac crest bone biopsies from 94 individuals: 46 women (ages 18-96, mean age 60.8 years) and 48 men (ages 23-92, mean age 59.5 years). Excluded from the study were all individuals with known osteoporotic lumbar vertebral fractures and renal, hepatic, or malignant diseases. Prior to collagen analysis the biopsies were scanned in a pQCT scanner for density assessment and then tested biomechanically. The results showed a decline in apparent bone density with age (P < 0.0001), a decline in maximum stress, Young's modulus, and energy absorption with age (P < 0.001). Concomittantly, there was an age-related decline in the intrinsic collagen content with age (P < 0.001). However, there were no biochemical modifications of the bone collagen during aging. There were no significant differences between women and men in the slopes of the regressions-curves. When multiple regression analyses were performed, only apparent bone density came out as a significant contributor in the correlation to biomechanical properties. Nevertheless, the decrease in bone collagen content with age might indicate an increase in the mineralization degree (probably due to decreased bone turnover) and thereby a change in material properties of bone. In conclusion, the present study has shown that loss of bone mass plays the major role in loss of bone strength. However, there is also a change in bone composition during normal aging, leading to a decrease in collagen content and an increase in the degree of mineralization. At this skeletal site, in a normal population there was no change in the biochemical properties of bone collagen.

Adolescent↗
PubMed2002

Association between a functional interleukin-6 gene polymorphism and peak bone mineral density and postmenopausal bone loss in women: the OFELY study.

Genetic factors play an important role in determining bone mass and several genes are involved in this process. Interleukin-6 (IL-6) is a candidate gene for regulation of bone mineral density (BMD) and it has been suggested recently that novel IL-6 -174 G/C allelic variants may be associated with peak BMD in young men and with bone resorption in elderly women. In this study, we assessed the relationships between IL-6 gene polymorphism, peak BMD, rate of postmenopausal BMD loss, and bone turnover in women. BMD was measured by dual-energy X-ray absorptiometry in 255 healthy premenopausal women, aged 31-57 years. BMD loss at the forearm was measured over 4 years in 298 healthy untreated postmenopausal women, 50-88 years (mean 64 years). We also measured levels of serum osteocalcin, bone alkaline phosphatase, and N-propeptide of type I collagen for bone formation and three markers of bone resorption, including urinary and serum C-terminal cross-linking telopeptide of type I collagen and urinary N-terminal telopeptide of type I collagen, in both pre- and postmenopausal women at baseline. In premenopausal women we found a significant association between IL-6 genotypes and BMD at the whole body (analysis of variance [ANOVA], p = 0.03), femoral neck (p = 0.03), trochanter (p = 0.014), Ward's triangle (p = 0.03), and total hip (p = 0.006), with subjects having the CC genotype showing 3%-7% higher BMD levels than their GG counterparts. However, after matching women with CC and GG genotypes for body height the differences decreased (2%-4%), and were no longer significant (p = 0.10-0.23). In postmenopausal women the mean rate of loss at the ultradistal radius was significantly associated with IL-6 genotypes (ANOVA, p = 0.049), with women having the CC genotype showing a significantly greater rate of bone loss (p < 0.05) compared with their GC and GG counterparts. After adjustment for weight changes, the difference in the rate of ultradistal radius bone loss between genotypes decreased and was not significant (p = 0.06 for CC vs. GG). A similar trend was observed for distal radius bone loss (p = 0.10, ANOVA), but not for the middle radius. We found no significant association between genotypes, bone turnover markers in premenopausal women, and either bone turnover or BMD in postmenopausal women. We conclude that this new functional IL-6 polymorphism was weakly associated with level of peak BMD and the rate of forearm trabecular postmenopausal bone loss in this cohort of healthy French women. IL-6 genotypes accounted only for a small proportion of the interindividual variation of both peak BMD and rate of bone loss and were not significant after adjustment for height and changes in body weight, respectively, suggesting that part of the effect may have been due to the differences in body size. Larger long-term studies are necessary to assess adequately the relationships between IL-6 genotype, rate of bone loss, and risk of fracture.

Adult↗
PubMed1999

Droloxifene does not blunt bone anabolic effects of prostaglandin E2, but maintains prostaglandin E2-restored bone in aged, ovariectomized rats.

Droloxifene (DRO) is a selective estrogen receptor modulator that prevents bone loss by inhibition of bone turnover associated with estrogen deficiency in both growing and aged female rats. The purposes of this study were to test: (a) whether DRO can maintain prostaglandin E2 (PGE2)-restored bone after discontinuation of PGE2 in aged, ovariectomized (ovx) rats; (b) if an inhibition of bone turnover by DRO reduces bone anabolic effects of PGE2; and (c) whether bone mass restored by PGE2 plus DRO can be maintained after discontinuation of both agents. Female rats at 12 months of age were sham-operated (sham) or ovx. Three months postsurgery, ovx rats were treated with either PGE2 (3 mg/kg per day, subcutaneously [s.c.]) alone, or PGE2 plus DRO (10 mg/kg per day, per os [p.o.]) for 2 months. Thereafter, the PGE2 or PGE2 plus DRO treatment was withdrawn and the rats were then treated with either vehicle or DRO for another 1.5 months. Using dual-energy X-ray absorptiometry (DXA), total lumbar vertebral bone mineral density (LV-BMD) was determined in vivo at months 0, 3, 5, and 6.5. At the end of the study, the rats were autopsied, and BMD of total femur, femoral shaft, distal femoral metaphysis, and proximal femur was determined ex vivo by DXA. Standard static and dynamic bone histomorphometric parameters were determined on the fourth lumbar vertebral body (L-4). At 3, 5, or 6.5 months postsurgery, LV-BMD decreased significantly (-15%, -19%, and -19%, respectively) in the vehicle-treated ovx rats compared with sham. Beginning at 3 months post-ovx, PGE2 alone or in combination with DRO for 2 months completely restored LV-BMD back to the sham level. There was no difference in LV-BMD in PGE2 alone or PGE2 plus DRO. Upon cessation of PGE2 treatment, a significant decrease in LV-BMD was observed in the PGE2-alone group (-12%). On the other hand, when DRO treatment was given after discontinuation of PGE2, the PGE2-restored LV-BMD was completely maintained. In the PGE2 plus DRO group, no loss in LV-BMD was observed after cessation of either PGE2 alone or both PGE2 and DRO. However, treatment with DRO following 2 months of PGE2 plus DRO further increased LV-BMD (+10%). At the end of the study, ex vivo femoral BMD data confirmed the observation in lumbar vertebrae. Histomorphometric results of L-4 indicated that loss in bone mass after cessation of PGE2 in PGE2 alone group was associated with increased bone turnover. Treatment with DRO in the maintenance phase inhibited bone turnover and prevented bone loss induced by withdrawal of PGE2. Trabecular bone mass was maintained in the PGE2 plus DRO followed by vehicle group and further increased in the PGE2 plus DRO followed by DRO groups. We found that: (a) DRO is efficacious in maintaining PGE2-restored bone after discontinuation of PGE2; (b) DRO did not blunt the anabolic effects of PGE2; (c) bone loss occurred after cessation of treatment in the PGE2-alone group, whereas it was maintained after cessation of treatment in PGE2 plus DRO group; and (d) an additional anabolic effect was found in ovx rats treated with PGE2 plus DRO followed by DRO.

Absorptiometry, Photon↗
PubMed1999

Age-related changes in insulin-like growth factor I and II in human femoral cortical bone: lack of correlation with bone mass.

The concentration of insulin-like growth factor-I (IGF-I) in human cortical bone declines with age, but the relevance of this decline for cortical bone turnover and bone mass is unknown. In the present study, we simultaneously assessed the concentration of IGF-I and -II in cortical bone matrix and histomorphometric parameters of bone mass and bone turnover in 125 samples from the proximal human femur shaft. Bone width decreased by 27% and porosity increased by 100% in female cortical bone between the fourth and the ninth decade. Similar, but weaker, changes tended to occur in male cortical bone. The concentrations of both IGF species were correlated with the percentage of osteons undergoing bone remodeling. However, despite age-related decreases in both IGF species in men and in IGF-I in women, neither of the IGFs accounted for age-related or age-independent variability in cortical porosity or bone width. In conclusion, these data suggest that the local concentrations of IGF-I and -II are related to cortical bone turnover. In contrast, our study provides no evidence for a major role of bone matrix IGF-I and -II as determinants of cortical bone mass in elderly individuals. Whether other components of the IGF system may be stronger determinants of cortical bone loss remains to be determined.

Adult↗
PubMed1999

Histomorphometric studies show that bone formation and bone mineral apposition rates are greater in C3H/HeJ (high-density) than C57BL/6J (low-density) mice during growth.

High-density C3H/HeJ (C3H) and low-density C57BL/6J (B6) mice, with femoral bone density differing by 50%, were chosen as a model to investigate the mechanisms controlling peak bone density and to map peak bone density genes. The present longitudinal study was undertaken to further establish the bone biologic phenotypes of these two inbred strains of mice. To evaluate phenotypic differences in bone formation parameters in C3H and B6 mice between the ages of 6 and 26 weeks, undecalcified ground sections from the diaphyses of the tibia and femur were prepared from mice receiving two injections of tetracycline. Histomorphometric analyses revealed that the cortical bone area was significantly greater (16%-56%, p < 0.001) in both the femur and tibia of the C3H mice than in the B6 mice at all timepoints. This difference in cortical bone area was due to significantly smaller medullary areas in the C3H mice than in the B6 mice. The bone formation rates (BFR) at the endosteum in both the femur and tibia were significantly greater (28%-117%,p < 0.001) in the young C3H mice (6-12 weeks old) than in B6 mice. The higher bone formation in C3H mice was associated with higher values of the bone mineral apposition rate (25%-94%, p < 0.001), and was not associated with higher values of the forming surface length as measured by tetracycline label length. Similar interstrain differences in mineral apposition and bone formation rates were observed in the periosteum of the femur and tibia. In conclusion, the greater bone area in the high-density C3H mice vs. the low-density B6 mice was, in part, due to the greater periosteal and endosteal bone formation rates during growth in the C3H mice. Because the C3H and B6 mice were maintained under identical environmental conditions (diet, lighting, etc.), the observed interstrain differences in bone parameters were the result of the action of genetic factors. Consequently, these two inbred strains of mice are suitable as a model to identify genetic factors responsible for high bone formation rates.

Animals↗
PubMed2006

RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis.

OBJECTIVES: Receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) have been demonstrated to be critical regulators of osteoclast generation and activity. In addition, RANKL has been implicated as an important mediator of bone erosion in rheumatoid arthritis (RA). However, the expression of RANKL and OPG at sites of pannus invasion into bone has not been examined. The present study was undertaken to further elucidate the contribution of this cytokine system to osteoclastogenesis and subsequent bone erosion in RA by examining the pattern of protein expression for RANKL, OPG and the receptor activator of NF-kappaB (RANK) in RA at sites of articular bone erosion. METHODS: Tissues from 20 surgical procedures from 17 patients with RA were collected as discarded materials. Six samples contained only synovium or tenosynovium remote from bone, four samples contained pannus-bone interface with adjacent synovium and 10 samples contained both synovium remote from bone and pannus-bone interface with adjacent synovium. Immunohistochemistry was used to characterize the cellular pattern of RANKL, RANK and OPG protein expression immediately adjacent to and remote from sites of bone erosion. RESULTS: Cellular expression of RANKL protein was relatively restricted in the bone microenvironment; staining was focal and confined largely to sites of osteoclast-mediated erosion at the pannus-bone interface and at sites of subchondral bone erosion. RANK-expressing osteoclast precursor cells were also present in these sites. OPG protein expression was observed in numerous cells in synovium remote from bone but was more limited at sites of bone erosion, especially in regions associated with RANKL expression. CONCLUSIONS: The pattern of RANKL and OPG expression and the presence of RANK-expressing osteoclast precursor cells at sites of bone erosion in RA contributes to the generation of a local microenvironment that favours osteoclast differentiation and activity. These data provide further evidence implicating RANKL in the pathogenesis of arthritis-induced joint destruction.

Adolescent↗
PubMed2007

Effects of bone oscillator coupling method, placement location, and occlusion on bone-conduction auditory steady-state responses in infants.

OBJECTIVE: The aim of these experiments was to investigate procedures used when estimating bone-conduction thresholds in infants. The objectives were: (i) to investigate the variability in force applied using two common bone-oscillator coupling methods and to determine whether coupling method affects threshold estimation, (ii) to examine effects of bone-oscillator placement on bone-conduction ASSR thresholds, and (iii) to determine whether the occlusion effect is present in infants by comparing bone-conduction ASSR thresholds for unoccluded and occluded ears. DESIGN: Experiment 1A: The variability in the amount of force applied to the bone oscillator by trained assistants (n = 4) for elastic-band and hand-held coupling methods was measured. Experiment 1B: Bone-conduction behavioral thresholds in 10 adults were compared for two coupling methods. Experiment 1C: ASSR thresholds and amplitudes to multiple bone-conduction stimuli were compared in 10 infants (mean age: 17 wk) using two coupling methods. Experiment 2: Bone-conduction ASSR thresholds and amplitudes were compared for temporal, mastoid and forehead oscillator placements in 15 preterm infants (mean age: 35 wk postconceptual age (PCA)). Experiment 3: Bone-conduction ASSR thresholds, amplitudes and phase delays were compared in 13 infants (mean age: 15 wk) for an unoccluded and occluded test ear. All infants that participated had passed a hearing screening test. RESULTS: Experiment 1A: Coupling method did not significantly affect the variability in force applied to the oscillator. Experiment 1B: There were no differences in adult bone-conduction behavioural thresholds between coupling methods. Experiment 1C: There was no significant difference between oscillator coupling method or significant frequency x coupling method interaction for ASSR thresholds or amplitudes in the young infants tested. However, there was a nonsignificant 9-dB better threshold at 4000 Hz for the elastic-band method. Experiment 2: Mean bone-conduction ASSR thresholds for the preterm infants were not significantly different for the temporal and mastoid placements. Mean ASSR thresholds for the forehead placement were significantly higher compared to the other two placements (12-18 dB higher on average). Mean ASSR amplitudes were significantly larger for the temporal and mastoid placements compared to the forehead placement. Experiment 3: There was no difference in mean ASSR thresholds, amplitudes or phase delays for the unoccluded versus occluded conditions. CONCLUSIONS: Trained assistants can apply an appropriate amount of force to the bone oscillator using either the elastic-band or hand-held method. Coupling method has no significant effect on estimation of bone-conduction thresholds; therefore, either may be used clinically provided assistants are appropriately trained. For preterm infants, there are no differences in ASSRs when the oscillator is positioned at the temporal or mastoid placement. However, thresholds are higher and amplitudes are smaller for the forehead placement, consequently, a forehead placement should be avoided for clinical testing. There does not appear to be a significant occlusion effect in young infants; therefore, it may be possible to do bone-conduction testing with ears unoccluded or occluded without applying a correction factor, although further research is needed to confirm this finding.

Acoustic Stimulation↗
PubMed2006

Digital spectral analysis of the drill-bone acoustic interface during temporal bone dissection: a qualitative cadaveric pilot study.

HYPOTHESIS: To qualitatively assess the different acoustic signatures of an otologic drill burr-bone interface during temporal bone dissection on full thickness calvarial and thin tegmen bone. BACKGROUND: An appreciable change in the sound generated by drilling occurs with progressive thinning of the bone during temporal bone dissection. To date, descriptions of this phenomenon are limited to a handful of subjective characterizations. Using digital power spectral analysis, interpretation of complex functions of time such as acoustic signals can be interpreted. METHODS: Acoustic data recorded from five cadaveric temporal bone dissections were studied using digital spectral analysis. RESULTS: The energy bandwidth concentration was between 5.0 and 7.9 kHz for full thickness bone using the cutting burr. Thin tegmen bone bandwidth concentration was lower, between 3.7 and 7.4 kHz and 3.9 and 6.0 kHz, using cutting and diamond burrs, respectively. Harmonic frequencies for thin tegmen bone-burr signals were 630 Hz. CONCLUSION: There is a consistent, reproducible qualitative difference in the spectral domain of the acoustic signature from the drill burr-bone interface between thick calvarial bone and thin tegmen bone caused by a higher harmonic peak interval and lower energy bandwidth concentration in the thinned tegmen bone-burr interface signal thus concentrating the acoustic signal within a more optimal frequency range for human perception. These results allow for a better understanding of the perceived change in sound with progressive thinning of bone with drilling. In addition, these data may allow the development of more realistic acoustic interfaces in virtual reality temporal bone dissection simulators.

Acoustics↗