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Bone marrow neutrophilia and suppressed bone turnover in human interleukin-6 transgenic mice. A cellular relationship among hematopoietic cells, osteoblasts, and osteoclasts mediated by stromal cells in bone marrow.

To elucidate the effect of interleukin-6 (IL-6) on bone and bone marrow (BM), human IL-6 transgenic mice (hIL-6 tgm) were produced. Their bone and BM were examined histologically, radiologically, histomorphometrically, and hematologically on a temporal basis. hIL-6 tgm showed histologically evident neutrophilia in BM. Increase in precursors of granulocytes and monocytes in hIL-6 tgm was demonstrated by an assay for colony forming unit in culture (CFU-C) of BM cells. Decrease in osteoblasts and osteoid and suppression of primary spongiosa formation were predominantly observed in hIL-6 tgm at 14 weeks old, the terminal stage of life for hIL-6 tgm. An assay for colony forming unit in fibroblastic (CFU-F) of BM cells revealed a decrease in osteoblast precursor (with regard to alkaline phosphatase-positive colonies) in hIL-6 tgm at 15 weeks old. Histomorphometry demonstrated a decrease of both osteoclast number and bone resorption in hIL-6 tgm. These results suggested that enhanced granulocytic hematopoiesis, suppressed bone turnover, and alteration of cellular population in stromal cells in BM occurred in hIL-6 tgm. Thus we provide new findings that facilitate understanding of cellular interrelationships among hematopoietic cells, osteoblasts, and osteoclasts mediated by stromal cells in BM.

Animals↗

Parietal bone agenesis with gracile bones and splenic hypoplasia/aplasia: clinico-pathologic report and differential diagnosis with review of cranio-gracile bone syndromes, "osteocraniostenosis" and Kleeblattschädel.

The findings in a newborn male with agenesis of parietal bones, gracile long bones, and hypoplasia of the spleen are presented. Although parietal agenesis is unique, the findings are compatible with 18 previously reported cases characterized by cranial hypomineralization, Kleeblatschädel, gracile bones, and splenic aplasia/hypoplasia, the nomenclature for which has been descriptive: gracile bone disorders, "osteocraniostenosis," "osteocraniosplenic syndrome." The term "osteocraniostenosis" may be inappropriate in that craniostenosis has been infrequently reported, a feature also of importance with respect to the pathogenesis of the Kleeblatschädel. The group likely reflects heterogeneous etiology and pathogenesis. Precedent, however, including animal models, justifies consideration of genetic aberrations, in particular, mutations in homeobox genes. (c) 2006 Wiley-Liss, Inc.

Abnormalities, Multiple↗

Association of oestrogen receptor alpha gene polymorphisms with postmenopausal bone loss, bone mass, and quantitative ultrasound properties of bone.

BACKGROUND: The gene encoding oestrogen receptor alpha (ESR1) appears to regulate bone mineral density (BMD) and other determinants of osteoporotic fracture risk. OBJECTIVE: To investigate the relation between common polymorphisms and haplotypes of the ESR1 gene and osteoporosis related phenotypes in a population based cohort of 3054 Scottish women. RESULTS: There was a significant association between a common haplotype "px", defined by the PvuII and XbaI restriction fragment length polymorphisms within intron 1 of the ESR1 gene, and femoral neck bone loss in postmenopausal women who had not received hormone replacement therapy (n = 945; p = 0.009). Annual rates of femoral neck bone loss were approximately 14% higher in subjects who carried one copy of px and 22% higher in those who carried two copies, compared with those who did not carry the px haplotype. The px haplotype was associated with lower femoral neck BMD in the postmenopausal women (p = 0.02), and with reduced calcaneal broadband ultrasound attenuation (BUA) values in the whole study population (p = 0.005). There was no association between a TA repeat polymorphism in the ESR1 promoter and any phenotype studied, though on long range haplotype analysis subjects with a smaller number of TA repeats who also carried the px haplotype had reduced BUA values. CONCLUSIONS: The ESR1px haplotype is associated with reduced hip BMD values and increased rates of femoral neck bone loss in postmenopausal women. An association with BUA may explain the fact that ESR1 intron 1 alleles predict osteoporotic fractures by a mechanism partly independent of differences in BMD.

Alleles↗

CFU-GM content of bone marrow graft correlates with time to hematologic reconstitution following autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide-purged bone marrow.

Autologous bone marrow transplants (BMTs) can repopulate the hematologic system of patients treated with marrow-ablative chemotherapy and/or radiotherapy. However, treatment of the bone marrow graft to eliminate residual tumor cells prior to reinfusion can delay the return of peripheral blood elements, presumably from damage to or loss of hematopoietic stem cells responsible for hematologic recovery. To develop a model predictive of hematologic recovery, we studied the progenitor cell contents of 4-hydroperoxycyclophosphamide (100 micrograms/mL)-purged bone marrow grafts of 40 consecutive patients undergoing autologous BMT at this center. Granulocyte-macrophage colonies (CFU-GM) were grown from all grafts after treatment with this chemotherapeutic agent, but erythroid (BFU-E) and mixed (CFU-GEMM) colonies were grown from only 44% and 33% of the grafts respectively. The recovery of CFU-GM after purging ranged from 0.07% to 23%. The logarithm of CFU-GM content of the treated grafts was linearly correlated with the time to recovery of peripheral blood leukocytes (r = -0.80), neutrophils (r = -0.79), reticulocytes (r = -0.60), and platelets (r = -0.66). The CFU-GM content of purged autologous bone marrow grafts may reflect the hematopoietic stem cell content of the grafts and thus predict the rate of hematologic recovery in patients undergoing autologous BMT.

Adolescent↗

Bone assessment in elderly women: what does a low bone ultrasound result tell us about bone mineral density?

Access to dual energy X-ray absorptiometry (DXA) can prove difficult for frail or elderly patients, and bone ultrasound may offer a practical alternative. Even after adjustment for bone mineral density (BMD), ultrasound readings are able to predict hip fracture in elderly women. We consider how bone ultrasound might contribute to bone assessment in a clinical setting. DXA remains the gold standard for bone assessment, with osteoporosis defined as a BMD result more than 2.5 S.D. below the young adult mean. Using an equivalent approach we defined an osteoporotic ultrasound result as broadband ultrasound attenuation (BUA)<54 dB/MHz. In 73 women aged 29-86 (mean 65) years DXA was used to measure BMD at lumbar spine and hip, and ultrasound to measure BUA at the heel. Correlation of BUA with BMD at femoral neck (r=0.64, P<0.001), and lumbar spine (r=0.55, P<0.001) was consistent with previously reported figures for this ultrasound system. All subjects with BUA below the 54 dB/MHz threshold value were shown to have low femoral neck BMD. Women (42%) aged over 65, but only 18% of younger women had low BUA results. In women over 65 years of age measurements of BUA achieved a sensitivity of 61% and specificity of 100% in prediction of low femoral neck BMD. Although a normal BUA did not exclude an osteoporotic BMD result at hip or lumbar spine, a low BUA appeared a highly specific predictor of low BMD at these sites. Since all those women identified as having a low BUA at the heel also had low BMD results, ultrasound appeared to identify a subgroup of elderly patients at a very high risk of fracture.

Journal Article↗

Effects of vertebral bone fragility and bone formation rate on the mineralization levels of cancellous bone from white females.

Back-scattered electron microscopy was used to study mineralization levels of human iliac cancellous bone of white females (N = 49). Mineralization levels were assessed by converting bone pixel grayscale levels to atomic number (Z) using known calibration standards. The data set consisted of bone biopsies from normal and vertebral fracture subjects that had either high or low values for bone formation rate (BFR(s)) within their respective groups (fracture/low BFR(s), N = 12; fracture/high BFR(s), N = 10; normal/low BFR(s), N = 12; normal/high BFR(s), N = 15). The following three measures of mineralization were quantitatively determined for each specimen: an overall mean mineralization (Z(mean)), the mineralization of trabecular packets deep within the interior of trabeculae (Z(deep)), and the mineralization of superficial exterior packets (Z(superficial)). Two-way analysis of variance revealed that the high BFR(s) group had a significantly lower Z(superficial) than the low BFR(s) group [mean (SD) 10.383 (0.270) vs. 10.563 (0.289)], and there was no significant interaction. BFR(s) had no effect on Z(mean) or Z(deep). For the pooled data, Z(deep) was significantly higher than Z(superficial) [10.866 (0.242) vs. 10.471 (0.291)]. There was no significant difference in Z(mean), Z(deep), or Z(superficial) between normals and those with vertebral fracture, but the standard deviations of the mineralization measures in the fracture group were at least double that of the normal group. Frequency histograms show that the two groups have fundamentally different mineralization distributions. The normal group demonstrates typical Gaussian distributions centered around the mean, and the distributions of the fracture group are bimodal, with peaks occurring at either the high or low tails of the distributions of the normal group. We hypothesize that both low and high patterns of mineralization might detrimentally affect bone material properties, with low mineralization levels causing reduced stiffness and strength and high mineralization resulting in reduced fracture toughness. The degree to which the mineralization differences may affect strength and stiffness of individual elements is estimated. The higher standard deviations of mineralization measures in the fracture group may reflect an inability to properly regulate trabecular level stress and strain. Forward stepwise regression analysis showed significant relationships between Ob.S/OS and both Z(superficial) and Z(mean), suggesting that the osteoblast may play an important role in regulating mineralization.

Aged↗

Graft incorporation within the tibial bone tunnel after anterior cruciate ligament reconstruction with bone-patellar tendon-bone autograft.

We described histologic changes in patellar tendon autografts that occur over time within the tibial tunnel in specimens harvested from patients undergoing revision anterior cruciate ligament reconstruction. Ten patients, averaging 21.2 years of age, were divided into two groups based on the time period between their original and revision surgery: early revision (less than 1 year, four patients) and late revision (more than 1 year, six patients). Among the early revision group, the tendon within the tunnel showed increased cellularity and random collagen bundles. A specimen from the shortest early revision case revealed a normal original bone-tendon junction, whereas others showed an obscured structure. Between the tendon and the tunnel wall, granulation tissue was seen and the bone-tendon junction was still immature. In the late revision group, the tendon appeared similar to normal ligament. The original bone-tendon junction was not seen, and the tendon continued completely to the tunnel wall with Sharpey-like fibers. Observations in the early revision group suggest that tendon remodeling and bone-tendon integration continue for at least several months after transplantation. The original bone-tendon junction appears to have shifted to the proximal patellar tendon-tunnel wall junction with time. These findings are in agreement with prior animal studies.

Adolescent↗

Biochemical properties of cortical allograft bone using a new method of bone strength measurement. A comparison of fresh, fresh-frozen and irradiated bone.

There have been conflicting reports on the effects of gamma irradiation on the material properties of cortical allograft bone. To investigate changes which result from the method of preparation, test samples must be produced with similar mechanical properties to minimise variations other than those resulting from treatment. We describe a new method for the comparative measurement of bone strength using standard bone samples. We used 233 samples from six cadavers to study the effects of irradiation at a standard dose (28 kGy) alone and combined with deep freezing. We also investigated the effects of varying the dose from 6.8 to 60 kGy (n = 132). None of the treatments had any effect on the elastic behaviour of the samples, but there was a reduction in strength to 64% of control values (p < 0.01) after irradiation with 28 kGy. There was also a dose-dependent reduction in strength and in the ability of the samples to absorb work before failure. We suggest that irradiation may cause an alteration in the bone matrix of allograft bone, but provided it is used in situations in which loading is within its elastic region, then failure should not occur.

Adolescent↗

Serum bone GLA-protein is not a sensitive marker of bone turnover in Paget's disease of bone.

Serum bone Gla-protein (sBGP) was measured in 32 patients with untreated Paget's disease of bone. Despite clinical and biological symptoms of active disease in all patients, sBGP was normal in 13/32 patients (41%). There was a striking discrepancy between the moderate increase of sBGP above normal values (11.4 +/- 4.5 vs 6.0 +/- 2.1 ng/ml) and the marked increase of both serum alkaline phosphatase (sAP) and urinary hydroxyproline (uOHP). sBGP was weakly correlated with sAP (r = 0.50, p less than 0.01), uOHP (r = 0.48, p less than 0.01) and with the extension of the disease (r = 0.48, p less than 0.01). We conclude that sBGP is not a sensitive marker of bone turnover in patients with Paget's disease of bone, and should be interpreted with caution in this condition.

Alkaline Phosphatase↗

Comparison of two phosphoproteins in chicken bone and their similarities to the mammalian bone proteins, osteopontin and bone sialoprotein II.

Two phosphorylated proteins of approximately 66 kDa and approximately 60 kDa mass with different DEAE-Sephacel elution patterns were isolated from chicken bone and were shown to be genetically distinct by both biochemical and immunological analysis. A tryptic peptide from the 60 kDa protein was identified that was similar to a sequence of the rat bone sialoprotein II. Both proteins showed RGD inhibited cell-attachment with the MG-63 osteosarcoma cell, and the approximately 66 kDa phosphoprotein appeared to promote cell adhesion better than human vitronectin. The two phosphoproteins appear to share functional and biochemical characteristics and to be homologous to the mammalian bone phosphoproteins, osteopontin and bone sialoprotein II.

Amino Acid Sequence↗

Autogenous onlay bone grafts fixed with screw implants for the treatment of severely resorbed maxillae. Radiographic evaluation of preoperative bone dimensions, postoperative bone loss, and changes in soft-tissue profile.

Thirty patients with severely resorbed edentulous maxillae underwent combined treatment of iliac bone onlay graft and titanium implants. The patients were followed for 3 years. They were radiographically examined before surgery to evaluate the bone volume at the intended implant sites. Only 13/156 implant sites were suitable for implant insertion. The bone level at the implant surfaces was evaluated after 6 months and 1, 2, and 3 years, respectively. There was a continuing decrease of the bone level throughout the follow-up period with a mean loss of 4.9 mm after 3 years and with no difference between sexes. Twenty-six implants were radiographically examined before removal, and only three of these implant sites showed radiographic signs of failure. The soft-tissue profile was analyzed cephalometrically by the subtraction technique. The upper lip generally moved inward and the apex of the nose and the columella downward and inward. The anterior facial height increased in most of the patients, resulting in a downward and inward change of the lower lip, the mentolabial sulcus, the soft-tissue pogonion, and the soft-tissue gnathion.

Adult↗

Estimation of skeletal bone mineral density by means of the trabecular pattern of the alveolar bone, its interdental thickness, and the bone mass of the mandible.

OBJECTIVE: We sought to evaluate the use of the alveolar trabecular pattern, the mandibular alveolar bone mass (MABM) measured by photodensitometry, and the interdental alveolar thickness for prediction of the skeletal bone mineral density (BMD). STUDY DESIGN: MABM and the coarseness of trabeculation were assessed by using periapical radiographs in 80 dentate women. The interdental alveolar thickness was measured on casts, and BMD of the forearm with dual X-ray absorptiometry. RESULTS: Significant correlations were found between skeletal BMD and MABM (r = 0.46, P <.001) as well as the coarseness of the trabeculation (r = 0.62, P <.001). The interdental alveolar thickness improved the correlation between skeletal BMD and MABM (R2 = 0.44, P <.001). Age, but not interdental thickness, improved the correlation between the coarseness of trabeculation and skeletal BMD (R2 = 0.52, P <.001). CONCLUSION: Evaluation of the coarseness of trabeculation of the alveolar bone as seen on intraoral radiographs is a helpful clinical indicator of skeletal BMD and better than densitometric measurements of the alveolar bone. Dense trabeculation is a strong indicator of high BMD, whereas sparse trabeculation may be used to predict low BMD.

Absorptiometry, Photon↗

Endogenous levels of serum estradiol and sex hormone binding globulin determine bone mineral density, bone remodeling, the rate of bone loss, and response to treatment with estrogen in elderly women.

A total of 489 elderly women aged 65-75 yr who participated in a 3-yr, randomized, blinded osteoporosis trial underwent measurements of serum estradiol, bioavailable estradiol, and SHBG. At baseline, bone mineral density (BMD) was lower at the femoral sites (7-19%, P < 0.05), total body (6-8%, P < 0.05), and spine (5-9%, P = 0.2) in women in the lowest tertile for serum total estradiol [<9 pg/ml (33 pmol/liter)], serum bioavailable estradiol [<2.4 pg/ml (8.8 pmol/liter)], or highest tertile for serum SHBG (>165 nmol/liter), compared with women in the highest tertiles of total estradiol [>13.3 pg/ml (49 pmol/liter)] and bioavailable estradiol [>4 pg/ml (14 pmol/liter)] or lowest tertile for SHBG (<113 nmol/liter). Bone markers were increased in women in the lowest tertile for serum total estradiol (not significant) and bioavailable estradiol (P < 0.05) and highest tertile for SHBG (P < 0.05). In the longitudinal study, the rate of bone loss in the placebo group was significantly higher in total body (P < 0.05) and spine (P < 0.05) in women in the lowest tertile, compared with the highest tertile of serum bioavailable estradiol. After treatment with conjugated equine estrogens 0.625 mg/d, the increase in BMD was 4-6% higher at the femoral sites (P < 0.05), total body (P < 0.05), and spine (not significant), in the lowest tertile, compared with the highest tertile of serum bioavailable estradiol or highest tertile, compared with the lowest tertile of serum SHBG. In summary, small variations in endogenous serum estradiol and high serum SHBG determine differences in BMD and rate of bone loss in elderly women and also affect the response to treatment with estrogen. Women with a serum estradiol level of less than 9 pg/ml (33 pmol/liter) are optimal candidates for estrogen therapy for osteoporosis prevention.

Aged↗

Percutaneous treatment of long bone nonunions: the use of autologous bone marrow and allograft bone matrix.

Sixty-six patients with 69 "stiff" nonunions (no gross motion) of long bones were entered into a prospective study. The only therapeutic intervention was the percutaneous administration of a mixture of autologous bone marrow and allograft demineralized bone matrix on an outpatient basis. Sixty-one of the percutaneous treatments (88%) resulted in union at an average of 8.1 months (range: 2 months to 3 years). This method of treating nonunions is as successful as standard iliac crest autologous bone grafting and offers the distinct advantages of decreased morbidity, reduced costs, and shorter hospital stay.

Adolescent↗

Bone morphogenetic protein receptors and bone morphogenetic protein signaling are controlled by tumor necrosis factor-alpha in human bone cells.

Bone morphogenetic proteins (BMP) stimulate osteoblast differentiation by signal transduction via three BMP receptors (BMPR-IA, -IB and -II), whereas the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) has been shown to suppress osteoblast differentiation. Although the mechanisms which regulate the BMPR are not yet known, it is possible that they may be negatively controlled by TNF-alpha, thereby inhibiting BMP-induced osteoblast differentiation. To test this hypothesis, we have examined the effects of TNF-alpha on BMPR-IA, -IB and -II expression and the functional consequences of this cytokine on BMPR-mediated functions in human bone cells. The results showed that although TNF-alpha down-regulated BMPR-IA and -II transcripts, it increased the level of BMPR-IB mRNA via a MAPK-dependent pathway. In marked contrast, however, TNF-alpha nevertheless caused marked down-regulation of the expression of the BMPR-IB surface antigen specifically. Moreover, the cytokine-induced decrease in BMPR-IB expression was found to be associated with the concurrent presence of a 'soluble' form of this antigen in supernatants of TNF-alpha-treated cultures. Furthermore, the TNF-alpha-induced loss of BMPR-IB was found to ablate BMP-2-stimulated bone cell functions, including phosphorylation of Smad1/5/8, alkaline phosphatase activity and osteocalcin expression. In conclusion, our study has provided evidence, for the first time, that BMPR can be differentially modulated by TNF-alpha at both the post-transcriptional and post-translational levels, with the TNF-alpha-induced shedding of the BMPR-IB antigen associated with a significantly diminished response to BMP-2 in vitro.

Antigens↗

Effect of growth hormone on bone: bone mineral density, trabecular bone volume, and alkaline phosphatase improve or are restored in the dwarf rat treated with growth hormone.

Studies were performed to determine whether serum total alkaline phosphatase (SAP), an index of bone formation; body weight; total body bone mineral density (BMD), measured by dual-energy X-ray absorptiometry; and tibial trabecular bone volume (TBV), measured by histomorphometry, are reduced in 2-week-old female sexually immature Lewis dwarf (dw/dw) rats (DW-CT, n = 9) with isolated growth hormone (GH) deficiency and, if so, whether recombinant human GH (rhGH), 200 micrograms/day subcutaneously for 4 weeks (DW-GH, n = 7), restores them. Studies were also performed to determine if 30% dietary restriction in 2-week-old female Lewis rats (LW-DR, n = 11) alters SAP, body weight, total BMD, or TBV compared with pair-fed controls (LW-CT, n = 7) given an ad libitum diet. Mean SAP (91 +/- 5 versus 109 +/- 5 U/l), body weight (102 +/- 11 versus 140 +/- 10 g), total BMD (88.5 +/- 0.3 versus 101.4 +/- 2.0 mg/cm2), and TBV (19.0 +/- 1.0 versus 27.0 +/- 1.4%) were significantly lower in DW-CT than in LW-CT animals, p < 0.05. In DW-GH, rhGH significantly increased mean SAP (130 +/- 7 U/l), body weight (133 +/- 10 g), total BMD (92.7 +/- 1.3), and TBV (24.0 +/- 1.9) compared with DW-CT animals. Compared with LW-CT rats, mean body weight and TBV were not different, but mean SAP was significantly higher (p < 0.01) and mean total BMD was significantly lower (p < 0.003) in DW-GH rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗

Percutaneous reaming of simple bone cysts in children followed by injection of demineralized bone matrix and autologous bone marrow.

The authors report the successful treatment of 19 patients (mean age 10 years) with active unicameral bone cysts using a combination of percutaneous reaming and injection of a mixture of demineralized bone matrix and autologous bone marrow. Follow-up ranged from 12 to 42 months (mean 28 months). All patients were asymptomatic at the latest follow-up. Two required a second intervention to accomplish complete cyst healing. Radiographic outcome was improved in all patients according to the Neer classification at the latest follow-up. There were no significant complications related to the procedure, nor did any fracture occur after initiation of the above regimen.

Adolescent↗

Bone metabolism after human parturition and the effect of lactation: longitudinal analysis of serum bone-related proteins and bone mineral content of the lumbar spine.

A prospective study was performed to investigate postpartum changes in human bone metabolism and the effects of lactation on them. The subjects consisted of two groups: 13 women who stopped breast-feeding within 3 months postpartum (short-term group) and 14 women who continued breast-feeding for more than 6 months postpartum (long-term group). Serum carboxyl-terminal propeptide of type I procollagen (PICP), carboxyl terminal cross-linked telopeptide of type I collagen (ICTP), and bone gla protein (BGP) were measured prepartum, and at 5 days, 1 month, 3 months and 9 months postpartum. Lumbar BMD was measured at 3-7 days, 3 months and 9 months postpartum. Between prepartum and 3 months postpartum, the values and variations in the markers were essentially the same in both groups. PICP was maintained at a constant and significantly higher level than the control value. In contrast, ICTP had increased markedly at 5 days postpartum, gradually decreasing thereafter. BGP was low prepartum and gradually increased. At 9 months postpartum, PICP and ICTP decreased to the control values in the short-term group. The postpartum time course of lumbar BMD showed a significant decrease in both groups at 3 months postpartum. Recovery to the puerperal level was seen at 9 months postpartum in the short-term group but not in the long-term group. In conclusion, bone resorption is stimulated by parturition as well as lactation resulting in postpartum loss of lumbar BMD.

Adult↗