bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in Runx2/Cbfa1 Expression and Activity During Osteoblastic Differentiation of Human Bone Marrow Stromal Cells
Authors: Shui Chaoxiang , Spelsberg Thomas C , Riggs B Lawrence , Khosla Sundeep 
Published: April 2006

Abstract
Runx2/Cbfa1 has been identified as a “master gene” controlling osteoblast differentiation. However, its role in inducing the osteoblast phenotype has been characterized primarily in rodent systems. Thus, we examined Runx2/Cbfa1 messenger RNA, protein, and activity levels during osteoblastic differentiation of human bone marrow stromal (BMSC) cells. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that the expression of alkaline phosphatase and osteocalcin mRNAs increased in a time-dependent manner with the development of the osteoblast phenotype by these cells (hMS2–15). Type II Runx2/Cbfa1 messenger RNA was found to be constitutively expressed in hMS2–15 cells and not altered during differentiation; there was no detectable expression of the type I Runx2/Cbfa1 transcript. Interestingly, despite the absence of any change in Runx2/Cbfa1 messenger RNA levels during osteoblastic differentiation of these cells, the activity of Runx2/Cbfa1, as assessed by binding to the osteoblast-specific cis-acting element 2 (OSE2), increased markedly at all time-points examined, with the highest activity level seen at day 7. Similar results were observed in primary cultures of less differentiated human marrow-derived mesenchymal stem cells. Immunoprecipitation and Western blot analysis revealed that whereas there was no increase in Runx2/Cbfa1 protein levels with differentiation in hMS2–15 cells, there was an increase in Runx2/Cbfa1 phosphorylation. Thus, in contrast to rodent systems where osteoblast differentiation is associated with increased synthesis of Runx2/Cbfa1, we find that in human BMSC, osteoblastic differentiation is associated primarily with increases in Runx2/Cbfa1 activity, without a change in messenger RNA or protein levels. Our findings also show that the increase in Runx2/Cbfa1 activity occurs through a posttranslational mechanism involving phosphorylation of key residues.
Evaluation of Bone Mineral Density and Fat-Lean Distribution in Patients With Multiple Myeloma in Sustained Remission
Authors: Roux S , Bergot C , Fermand JP , Frija J , Brouet JC , Mariette X 
Published: April 2006

Abstract
To study the usefulness of bone mineral density (BMD) in the follow-up of myeloma (MM) patients, BMD was evaluated in 44 MM patients in sustained remission for at least 2 years (35.4 ± 10.5 months) after high-dose or conventional chemotherapy in a retrospective study. Patients never received bisphosphonates before or during the follow-up. Patients underwent lumbar spine (LS) BMD and a whole body (WB) BMD testing before therapy and at least once in the remission period. At baseline, mean LS BMD was 0.863 ± 0.026 g/cm2, mean lumbar Z-score was −1.45 SD. LS BMD significantly increased from baseline by 5 ± 1.8%, 9.3 ± 1.7%, and 14 ± 1.9% at 1, 2, and 3 years, respectively. The percentage of patients with a T-score below 2.5 SD decreased from 39% at baseline to 18.5% at 3 years. Compared with baseline, WB BMD decreased by −2.8 ± 0.5%, −2.6 ± 0.7%, and −1.7 ± 0.6% at 1, 2, and 3 years, respectively. Mean percentage change of the fat compartment increased from baseline by +28.4 ± 7.1% at the trunk, and + 17.1 ± 5% in peripheral areas at 3 years. In conclusion, in MM patients in remission after chemotherapy, LS BMD progressively increased after a mean follow-up of 3 years. These patients never received bisphosphonates, so this increase was related to the anti-myeloma treatment. The major effect on BMD was observed at the LS, which is primarily composed of trabecular bone containing the bone marrow. Interestingly, a drastic increase of the fat content was also observed. These results underlined that BMD and fat-lean evaluation could be of interest in the follow-up of MM patients.
Positive Linear Growth and Bone Responses to Growth Hormone Treatment in Children With Types III and IV Osteogenesis Imperfecta: High Predictive Value of the Carboxyterminal Propeptide of Type I Procollagen
Authors: Marini Joan C , Hopkins Elizabeth , Glorieux Francis H , Chrousos George P , Reynolds James C , Gundberg Caren M , Reing C Michael 
Published: April 2006

Abstract
Extreme short stature is a cardinal feature of severe osteogenesis imperfecta (OI), types III and IV. We conducted a treatment trial of growth hormone in children with OI and followed linear growth velocity, bone metabolism markers, histomorphometrics, and vertebral bone density. Twenty-six children with types III and IV OI, ages 4.5–12 years, were treated with recombinant growth hormone (rGH), 0.1–0.2 IU/kg per day for 6 days/week, for at least 1 year. Length, insulin-like growth factor (IGF-I), insulin-like growth factor binding protein (IGFBP-3), bone metabolic markers, and vertebral bone density by DXA were evaluated at 6-month intervals. An iliac crest biopsy was obtained at baseline and 12 months. Approximately one-half of the treated OI children sustained a 50% or more increase in linear growth over their baseline growth rate. Most responders (10 of 14) had moderate type IV OI. All participants had positive IGF-I, IGFBP-3, osteocalcin, and bone-specific alkaline phosphatase responses. Only the linear growth responders had a significant increase in vertebral DXA z-score and a significant decrease in long bone fractures. After 1 year of treatment, responders' iliac crest biopsy showed significant increases in cancellous bone volume, trabecular number, and bone formation rate. Responders were distinguished from nonresponders by higher baseline carboxyterminal propeptide (PICP) values (p &lt; 0.05), suggesting they have an intrinsically higher capacity for collagen production. The results show that growth hormone can cause a sustained increase in the linear growth rate of children with OI, despite the abnormal collagen in their bone matrix. In the first year of treatment, growth responders achieve increased bone formation rate and density, and decreased fracture rates. The baseline plasma concentration of PICP was an excellent predictor of positive response.
Expression of Either NF-κB p50 or p52 in Osteoclast Precursors Is Required for IL-1-Induced Bone Resorption
Authors: Xing Lianping , Carlson Louise , Story Beryl , Tai Zhenxing , Keng Peter , Siebenlist Ulrich , Boyce Brendan F 
Published: April 2006

AbstractInterleukin (IL)-1 is implicated in postmenopausal- and inflammation-mediated bone loss. Its expression is regulated by NF-κB and vice versa. To examine the role of NF-κB p50 and p52 (they are required for osteoclast formation during embryonic development) in IL-1-induced resorption, we used various NF-κB knockout (KO) mice, including p50−/− and p52−/− single KO, p50−/− and p52+/− (3/4KO), and p50−/− and p52−/− double KO (dKO) mice. IL-1 increased blood calcium and bone resorption in wild-type (wt), p50, and p52 single KO mice, but not in 3/4KO or dKO mice. Osteoclast formation was impaired in bone marrow cultures from 3/4KO compared with single KO and wt mice treated with IL-1. IL-1 receptor expression was similar in colony forming unit-granulocyte macrophage (CFU-GM) colony cells from wt and dKO mice. However, IL-1 promoted CFU-GM colony formation and survival as well as the formation, activity, and survival of osteoclasts generated from these colonies from wt mouse splenocytes, but not from dKO splenocytes. No difference in expression of the osteoclast regulatory cytokines, RANKL, and OPG, was observed in osteoblasts from wt and dKO mice. Thus, expression of either NF-κB p50 or p52 is required in osteoclasts and their precursors, rather than osteoblasts, for IL-1-mediated bone resorption.
Expression of RANKL and OPG Correlates With Age-Related Bone Loss in Male C57BL/6 Mice
Authors: Cao Jay , Venton Laura , Sakata Takeshi , Halloran Bernard P 
Published: April 2006

Abstract
Osteoblasts regulate the recruitment and activity of osteoclasts through expression of RANKL and osteoprotegerin (OPG). To determine whether expression of RANKL and OPG change with age and how these changes relate to the bone loss of aging, we measured bone mass and cancellous volume, and expression of RANKL, OPG, alkaline phosphatase (AP), osteocalcin (OC), and alpha I collagen (COLL) in whole bone and osteoblast-like cells in culture using 6-week- (young), 6-month- (adult), and 24-month-old (old) mice. Cancellous volume decreased by 20% from young to adult and by 52% from adult to old. RANKL mRNA levels in whole bone were 2.1-fold and 4.4-fold higher in adult and old mice, respectively, compared with young mice, whereas OPG mRNA levels decreased with age slightly. RANKL expression was negatively (r = −0.99) and OPG was positively (r = 0.92) correlated with cancellous bone volume. Expression of RANKL was higher and OPG lower in cells from older animals early in culture (day 7). With cell maturation, RANKL mRNA levels in cells from young and adult mice increased, whereas levels in cells from old animals decreased. By 21 and 28 days of culture, no differences were found in RANKL mRNA in osteoblast-like cells among different age groups. We conclude that expression of RANKL and OPG change with age in whole bone and in cultured osteoblast-like cells. These changes favor increased osteoclast over osteoblast activity, and may explain, in part, the imbalance in bone formation and resorption associated with aging.
Overexpression of RANKL Implicates IFN-β-Mediated Elimination of B-Cell Precursors in the Osteopetrotic Bone of Microphthalmic Mice
Authors: Roundy K , Smith R , Weis JJ , Weis JH 
Published: April 2006

Abstract
The microphthalmic (mi) mouse possesses a dominant negative mutation in the microphthalmia-associated transcript factor (MITF) transcription factor. These animals are characterized by reduced numbers of peripheral mast and natural killer (NK) cells, are osteopetrotic because of osteoclast reduction and malfunction, lack functional melanocytes, and are deficient for maturing B-cells within the bone marrow. Granulocyte precursor cells, however, are functionally maintained within the mi bone marrow. A central question has been whether the B-cell deficiency of the mi mouse marrow is caused by the absence of an MITF-controlled gene product or because of the compromised, osteopetrotic environment. In this report, we examined mi marrow by performing transcriptional mapping analyses of candidate genes whose products are instrumental for functional osteoclast and B-cell development. Surprisingly, the expression of a subset of such genes including RANKL, stromal-derived factor (SDF-1), B-cell lymphotactin chemokine (BLC), and RANK was dramatically enhanced in the mi marrow. Normal and mutant marrow were also analyzed by subtractive transcript cloning, which identified a number of known and unknown genes with altered transcriptional activity. One such unknown mouse gene possesses a human counterpart that is interferon-β (IFN-β) inducible, suggesting the osteopetrotic marrow is enriched for IFN-β, a cytokine that is known to eliminate B-cell precursors. A model is proposed suggesting excess RANKL sets off a cascade of cytokine production including IFN-β that leads to the preferential elimination of B-cell precursors in the marrow of osteopetrotic marrow.
Deficient Acquisition of Bone During Maturation Underlies Idiopathic Osteoporosis in Men: Evidence From a Three-Generation Family Study
Authors: Van Pottelbergh I , Goemaere S , Zmierczak H , De Bacquer D , Kaufman JM 
Published: April 2006

Abstract
To address the issue whether deficient acquisition of bone during maturation or adult-onset bone loss is primarily to blame for idiopathic osteoporosis in men, we assessed indices of bone mineral density and size, as well as biochemical markers of bone turnover in 61 probands (ages 20–65 years) with idiopathic osteoporosis (z-score ≤ −2.0 at the spine or hip), their first-degree relatives (n = 130), and age-matched controls. There was no indication of accelerated bone loss. Indeed, in probands, the observed bone deficit versus controls was unrelated to the age of probands, and indices of bone turnover were not significantly different from controls. On the other hand, a specific deficit in bone acquisition was suggested by findings of lower bone mineral density values in three generations of male and female relatives of the probands, including their offspring; bone turnover in relatives was not different from controls. The bone mineral density deficit was more pronounced in male compared with female relatives; approximately 60% of the sons had a spinal bone mineral density z-score of less than −2.0. There also was a skeletal site-specificity in probands and their male relatives with a larger areal bone mineral density deficit at the spine compared with the hip and the forearm. The deficit at the spine corresponded to a reduction of both volumetric bone mineral density and bone size; a similar less pronounced deficit in volumetric bone mineral density, but not in bone size, was observed at the femoral neck. These findings in probands and their first-degree relatives point toward a major contributory role of a genetically determined maturational defect in bone acquisition in the pathogenesis of idiopathic osteoporosis in men.
Relation of Androgen Receptor Gene Polymorphism to Bone Mineral Density and Fracture Risk in Early Postmenopausal Women During a 5-Year Randomized Hormone Replacement Therapy Trial
Authors: Salmén Timo , Heikkinen Anna-Mari , Mahonen Anitta , Kröger Heikki , Komulainen Marja , Pallonen Heli , Saarikoski Seppo , Honkanen Risto , Mäenpää Pekka H 
Published: April 2006

Abstract
In women, the influence of androgens on bone health is not clear. It has been suggested that the androgen receptor (AR) genotype is associated with bone mineral density and serum androgen levels in pre- and perimenopausal women, but the association between AR genotype, bone mineral density, and fracture risk has not been studied in postmenopausal women. Therefore, we studied whether AR polymorphism affects bone mineral density, bone mineral density change, or fracture risk in a 5-year randomized hormone replacement therapy (HRT) trial on 331 early postmenopausal women (mean baseline age, 52.7 ± 2.3 years). The participants consisted of two treatment groups: the HRT group (n = 151) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3, 100–300 IU + 93 mg calcium as lactate/day, and the non-HRT group (n = 180) received 93 mg calcium alone or in combination with vitamin D3, 100–300 IU/day for 5 years. Bone mineral density was measured from lumbar spine and proximal femur (DXA) before and after the 5-year trial. All new symptomatic, radiographically defined fractures were recorded during the follow-up. The length of CAG repeat in exon 1 of AR gene was evaluated after polymerase chain reaction (PCR) amplification. The subjects were divided into three repeat groups according to AR alleles. None of the baseline characteristics were associated with AR gene polymorphism and HRT treatment. The polymorphism did not influence the calculated annual changes of lumbar or femoral neck bone mineral density during the 5-year follow-up in the HRT (p = 0.926 and 0.146, respectively) or non-HRT (p = 0.818 and 0.917, respectively) groups. In all, 28 women sustained 33 fractures during the follow-up. Thus, the numbers of fractures were limited. The AR repeat length variation was not significantly associated with fracture risk in the HRT or non-HRT groups (p = 0.632 and 0.459, respectively; Cox proportional hazards model). In conclusion, AR gene polymorphism was not associated with baseline bone mineral density, 5-year bone mineral density change, or fracture risk in early postmenopausal Finnish women.
Effects of Vitamin D and Calcium Supplementation on Falls: A Randomized Controlled Trial
Authors: Bischoff Heike A , Stähelin Hannes B , Dick Walter , Akos Regula , Knecht Margrith , Salis Christian , Nebiker Matthias , Theiler Robert , Pfeifer Michael , Begerow Bettina , Lew Robert A , Conzelmann Martin 
Published: April 2006

Abstract
Specific receptors for vitamin D have been identified in human muscle tissue. Cross-sectional studies show that elderly persons with higher vitamin D serum levels have increased muscle strength and a lower number of falls. We hypothesized that vitamin D and calcium supplementation would improve musculoskeletal function and decrease falls. In a double-blind randomized controlled trial, we studied 122 elderly women (mean age, 85.3 years; range, 63–99 years) in long-stay geriatric care. Participants received 1200 mg calcium plus 800 IU cholecalciferol (Cal+D-group; n = 62) or 1200 mg calcium (Cal-group; n = 60) per day over a 12-week treatment period. The number of falls per person (0, 1, 2–5, 6–7, &gt;7 falls) was compared between the treatment groups. In an intention to treat analysis, a Poisson regression model was used to compare falls after controlling for age, number of falls in a 6-week pretreatment period, and baseline 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum concentrations. Among fallers in the treatment period, crude excessive fall rate (treatment − pretreatment falls) was compared between treatment groups. Change in musculoskeletal function (summed score of knee flexor and extensor strength, grip strength, and the timed up&go test) was measured as a secondary outcome. Among subjects in the Cal+D-group, there were significant increases in median serum 25-hydroxyvitamin D (+71%) and 1,25-dihydroxyvitamin D (+8%). Before treatment, mean observed number of falls per person per week was 0.059 in the Cal+D-group and 0.056 in the Cal-group. In the 12-week treatment period, mean number of falls per person per week was 0.034 in the Cal+D-group and 0.076 in the Cal-group. After adjustment, Cal+D-treatment accounted for a 49% reduction of falls (95% CI, 14–71%; p &lt; 0.01) based on the fall categories stated above. Among fallers of the treatment period, the crude average number of excessive falls was significantly higher in the Cal-group (p = 0.045). Musculoskeletal function improved significantly in the Cal+D-group (p = 0.0094). A single intervention with vitamin D plus calcium over a 3-month period reduced the risk of falling by 49% compared with calcium alone. Over this short-term intervention, recurrent fallers seem to benefit most by the treatment. The impact of vitamin D on falls might be explained by the observed improvement in musculoskeletal function.
Identification of a Novel Tandem Duplication in Exon 1 of the TNFRSF11A Gene in Two Unrelated Patients With Familial Expansile Osteolysis
Authors: Johnson-Pais Teresa L , Singer Frederick R , Bone Henry G , McMurray Cynthia T , Hansen Marc F , Leach Robin J 
Published: April 2006

Abstract
Familial expansile osteolysis (FEO) is a rare autosomal dominant disorder characterized by striking focal expansile osteolytic bone lesions and generalized osteopenia, often accompanied by characteristic early hearing loss and dental disease. The TNFRSF11A gene encodes the receptor activator of nuclear factor-κB (RANK), which has been demonstrated to be essential in bone remodeling and osteoclast differentiation. Identical insertional mutations in the first exon of RANK have been identified in all published FEO kindreds. The mutation is an 18 base pair tandem duplication in the sequence coding for the signal peptide of RANK, which causes an increase in NF-κB signaling. We report the identification and mutational analysis of two unrelated FEO patients. One had no family history of FEO, but presented with bilateral hearing loss at an early age, deterioration of teeth, and severe pain and swelling in the distal tibia before the age of 20. The second patient had a family history of FEO and exhibited an extensive expansile tibial lesion and lesions in one humerus and a phalanx. She also had early hearing loss and dental disease. Mutational analysis of the TNFRSF11A gene in our patients demonstrated an 18 base pair tandem duplication, one base proximal to the duplications previously reported. This novel mutation results in addition of the same six amino acids to the RANK signal peptide that has been observed previously. Further analysis of the exon 1 sequence demonstrated that it has the ability to form a stable secondary structure that may facilitate the generation of tandem duplications.
Reduced Levels of MMP-2 and TIMP-1 in Dyssegmental Dysplasia
Authors: Uchide Kiyoshi , Ueno Hirohisa , Takizawa Noboru , Okada Yasunori 
Published: April 2006

Abstract
Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were measured in a mild case of dyssegmental dysplasia. X-ray pictures of a female baby born vaginally at 39 weeks of gestation showed short, bent, dumbbell-shaped long bones of the limbs and profound dyssegmental ossification in the spine, findings characteristic of dyssegmental dysplasia. When the levels of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured, the levels of MMP-2 and TIMP-1 were significantly reduced. This case might provide a clue to disclose the etiology of dyssegmental dysplasia.
Autosomal Dominant Gnathodiaphyseal Dysplasia Maps to Chromosome 11p14.3-15.1
Authors: Tsutsumi Satoshi , Kamata Nobuyuki , Maruoka Yutaka , Ando Miki , Tezuka Osamu , Enomoto Shoji , Omura Ken , Nagayama Masaru , Kudo Eiji , Moritani Maki , Yamaoka Takashi , Itakura Mitsuo 
Published: April 2006

Abstract
Gnathodiaphyseal dysplasia (GDD) is a syndrome characterized by bone fragility, sclerosis of tubular bones, and cemento-osseous lesions of jawbones. Although some cases of this syndrome exist in families with autosomal dominant inheritance, the underlying gene has never been identified. We analyzed a large four-generation family with GDD by linkage analysis using genomic DNA from nine affected and six nonaffected family members. A genome-wide search using a set of highly polymorphic microsatellite markers showed evidence for linkage to chromosome 11p14.3-15.1. Two-point linkage analysis of microsatellite markers spanning this locus resulted in a maximum logarithm of odds (LOD) score of 2.70 with a recombination fraction (θ) of 0 at D11S1755, D11S1759, and D11S915, and a maximum LOD score of 3.01 at D11S4114 was obtained in multipoint linkage analysis. Haplotype analysis detected no recombination between GDD and six closely linked markers (D11S928, D11S1755, D11S4114, D11S1759, D11S915, and D11S929) and established the candidate interval of 8.7 cM on chromosome 11p for GDD. Although GDD has been considered to be a variation of osteogenesis imperfecta (MIM 166260), our results indicate that this syndrome is a new and distinct disease entity from other systemic bone diseases. Furthermore, these genetic markers are useful for presymptomatic diagnosis of GDD in some families and for identification of the GDD gene.