bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of Common Genetic Variants in Cathepsin K and Testing for Association With Bone Mineral Density in a Large Cohort of Perimenopausal Women From Scotland
Authors: Giraudeau Fabienne S , Mcginnis Ralph E , Gray Ian C , O'Brien Eamonn J , Doncaster Kim E , Spurr Nigel K , Ralston Stuart H , Reid David M , Wood John 
Published: April 2006

Abstract
BMD values in ∼3000 perimenopausal Scottish women were adjusted by regression to identify and account for nongenetic factors. Adjusted BMD values were not associated with simple tandem repeat (STR) markers or single nucleotide polymorphisms (SNPs) at the Cathepsin K (CTSK) locus. We present a thorough analysis of common CTSK polymorphisms and genetic relatedness among CTSK haplotypes.
Introduction: CTSK is a cysteine protease of the papain family and is thought to play a critical role in osteoclast-mediated bone degradation. Rare, inactivating mutations in CTSK cause pychodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature. However, there have been no studies of common genetic variants in CTSK and their possible association with bone density in the general population.
Materials and Methods: To identify common single nucleotide polymorphisms (SNPs) and simple tandem repeat (STR) polymorphisms in and around CTSK, we screened all CTSK exons, intron A, all intron-exon boundaries, and the putative CTSK promoter region in 130 random whites using both high-performance liquid chromatography (HPLC) and DNA sequencing. CTSK markers were genotyped in ∼3000 perimenopausal Scottish women whose hip and spine bone mineral density (BMD) had been measured by DXA. We performed linear regression analysis to identify and adjust for nongenetic predictors of BMD, and adjusted BMD values (regression residuals) were tested for association with individual CTSK markers and haplotypes by ANOVA and the composite haplotype method of Zaykin et al.
Results and Conclusions: We discovered two intronic SNPs (8% and 9% frequency), but no common exonic SNPs (&gt;1% frequency), and found that three STRs at the immediate 5′ end of the CTSK locus are highly polymorphic. The population frequencies of haplotypes defined by these five polymorphisms were estimated, and a cladogram was derived showing proximity of relationship and likely descent of the 30 most common CTSK haplotypes. Regression analyses revealed that approximately 39% of spine and 19% of hip rate of change in BMD was accounted for by nongenetic factors. For baseline BMD values in premenopausal women, nongenetic predictors explained 11% of the variance at the spine and 13% at the hip. Adjusted BMD values showed no statistically significant association with any of the individual CTSK polymorphisms or CTSK haplotypes.
Paracrine and Autocrine Signals Promoting Full Chondrogenic Differentiation of a Mesoblastic Cell Line
Authors: Locker Morgane , Kellermann Odile , Boucquey Marie , Khun Huot , Huerre Michel , Poliard Anne 
Published: April 2006

Abstract
The pluripotent mesoblastic C1 cell line was used under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to drive chondrogenesis. Sequential addition of two systemic hormones, dexamethasone and triiodothyronine, permits full chondrogenic differentiation. The cell intrinsic activation of the BMP signaling pathway and Sox9 expression occurring on mesoblastic condensation is insufficient for recruitment of the progenitors. Dexamethasone-dependent Sox9 upregulation is essential for chondrogenesis.
Introduction: Differentiation of lineage stem cells relies on cell autonomous regulations modulated by external signals. We used the pluripotent mesoblastic C1 cell line under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to induce differentiation of a precursor clone along the chondrogenic lineage.
Materials and Methods: C1 cells, cultured as aggregates, were induced toward chondrogenesis by addition of 10−7 M dexamethasone in serum-free medium. After 30 days, dexamethasone was replaced by 10 nM triiodothyronine to promote final hypertrophic conversion. Mature and hypertrophic phenotypes were characterized by immunocytochemistry using specific antibodies against types II and X collagens, respectively. Type II collagen, bone morphogenetic proteins (BMPs), BMP receptors, Smads, and Sox9 expression were monitored by reverse transcriptase-polymerase chain reaction (RT-PCR), Northern blot, and/or Western blot analysis.
Results and Conclusions: Once C1 cells have formed nodules, sequential addition of two systemic hormones is sufficient to promote full chondrogenic differentiation. In response to dexamethasone, nearly 100% of the C1 precursors engage in chondrogenesis and convert within 30 days into mature chondrocytes, which triggers a typical cartilage matrix. On day 25, a switch in type II procollagen mRNA splicing acted as a limiting step in the acquisition of the mature chondrocyte phenotype. On day 30, substitution of dexamethasone with triiodothyronine triggers the final differentiation into hypertrophic chondrocytes within a further 15 days. The chondrogenic process is supported by intrinsic expression of Sox9 and BMP family genes. Similarly to the in vivo situation, activation of Sox9 expression and the BMP signaling pathway occurred on mesoblastic condensation. After induction, BMP-activated Smad nuclear translocation persisted throughout the process until the onset of hypertrophy. After dexamethasone addition, Sox9 expression was upregulated. Dexamethasone withdrawal reversed the increase in Sox9 expression and stopped differentiation. Thus, Sox9 seems to be a downstream mediator of dexamethasone action.
Genetic Predisposition for Adult Lactose Intolerance and Relation to Diet, Bone Density, and Bone Fractures
Authors: Obermayer-Pietsch Barbara M , Bonelli Christine M , Walter Daniela E , Kuhn Regina J , Fahrleitner-Pammer Astrid , Berghold Andrea , Goessler Walter , Stepan Vinzenz , Dobnig Harald , Leb Georg , Renner Wilfried 
Published: April 2006

Abstract
Evidence that genetic disposition for adult lactose intolerance significantly affects calcium intake, bone density, and fractures in postmenopausal women is presented. PCR-based genotyping of lactase gene polymorphisms may complement diagnostic procedures to identify persons at risk for both lactose malabsorption and osteoporosis.
Introduction: Lactase deficiency is a common autosomal recessive condition resulting in decreased intestinal lactose degradation. A −13910 T/C dimorphism (LCT) near the lactase phlorizin hydrolase gene, reported to be strongly associated with adult lactase nonpersistence, may have an impact on calcium supply, bone density, and osteoporotic fractures in the elderly.
Materials and Methods: We determined LCT genotypes TT, TC, and CC in 258 postmenopausal women using a polymerase chain reaction-based assay. Genotypes were related to milk intolerance, nutritional calcium intake, intestinal calcium absorption, bone mineral density (BMD), and nonvertebral fractures.
Results: Twenty-four percent of all women were found to have CC genotypes and genetic lactase deficiency. Age-adjusted BMD at the hip in CC genotypes and at the spine in CC and TC genotypes was reduced by −7% to −11% depending on the site measured (p = 0.04). LCT(T/C−13910) polymorphisms alone accounted for 2–4 % of BMD in a multiple regression model. Bone fracture incidence was significantly associated with CC genotypes (p = 0.001). Milk calcium intake was significantly lower (−55%, p = 0.004) and aversion to milk consumption was significantly higher (+166%, p = 0.01) in women with the CC genotype, but there were no differences in overall dietary calcium intake or in intestinal calcium absorption test values.
Conclusion: The LCT(T/C−13910) polymorphism is associated with subjective milk intolerance, reduced milk calcium intake, and reduced BMD at the hip and the lumbar spine and may predispose to bone fractures. Genetic testing for lactase deficiency may complement indirect methods in the detection of individuals at risk for both lactose malabsorption and osteoporosis.
Expression and Activity of the CDK Inhibitor p57Kip2 in Chondrocytes Undergoing Hypertrophic Differentiation
Authors: Stewart Matthew C , Kadlcek Renata M , Robbins Paul D , Macleod James N , Ballock R Tracy 
Published: April 2006

Abstract
Growth plates ofp57-null mice exhibit several abnormalities, including loss of collagen type X (CollX) expression. The phenotypic consequences of p57 expression were assessed in an in vitro model of hypertrophic differentiation. Adenoviral p57 expression was not sufficient for CollX expression but did augment induction of CollX by BMP-2.
Introduction: During hypertrophic differentiation, chondrocytes pass from an actively proliferative state to a postmitotic, hypertrophic phenotype. The induction of growth arrest is a central feature of this phenotypic transition. Mice lacking the cyclin dependent-kinase inhibitor p57Kip2 exhibit several developmental abnormalities including chondrodysplasia. Although growth plate chondrocytes in p57-null mice undergo growth arrest, they do not express collagen type X, a specific marker of the hypertrophic phenotype. This study was carried out to investigate the link between p57 expression and the induction of collagen type X in chondrocytes and to determine whether p57 overexpression is sufficient for the induction of hypertrophic differentiation.
Materials and Methods: Neonatal rat epiphyseal or growth plate chondrocytes were maintained in an aggregate culture model, in defined, serum-free medium. Protein and mRNA levels were monitored by Western and Northern blot analyses, respectively. Proliferative activity was assessed by fluorescent measurement of total DNA and by3H-thymidine incorporation rates. An adenoviral vector was used to assess the phenotypic consequences of p57 expression.
Results and Conclusions: During in vitro hypertrophic differentiation, levels of p57 mRNA and protein were constant despite changes in chondrocyte proliferative activity and the induction of hypertrophic-specific genes in response to bone morphogenetic protein (BMP)-2. Adenoviral p57 overexpression induced growth arrest in prehypertrophic epiphyseal chondrocytes in a dose-dependent manner but was not sufficient for the induction of collagen type X, either alone or when coexpressed with the related CDKI p21Cip1. Similar results were obtained with more mature tibial growth plate chondrocytes. p57 overexpression did augment collagen type X induction by BMP-2. These data indicate that p57-mediated growth arrest is not sufficient for expression of the hypertrophic phenotype, but rather it occurs in parallel with other aspects of the differentiation pathway. Our findings also suggest a contributing role for p57 in the regulation of collagen type X expression in differentiating chondrocytes.
Fracture Risk in Monoclonal Gammopathy of Undetermined Significance
Authors: Melton L Joseph , Rajkumar S Vincent , Khosla Sundeep , Achenbach Sara J , Oberg Ann L , Kyle Robert A 
Published: April 2006

Abstract
To assess fractures in monoclonal gammopathy of undetermined significance (MGUS), the precursor of multiple myeloma, we followed 488 Olmsted County, MN, residents with MGUS in a retrospective cohort study. There was a 2.7-fold increase in the risk of axial fractures but no increase in limb fractures. The pathophysiologic basis for the increased axial fractures should be determined.
Introduction: Multiple myeloma is often preceded by monoclonal gammopathy of undetermined significance (MGUS). Fractures are common in myeloma as a result of lytic bone lesions, generalized bone loss, and elevated bone turnover from excessive cytokine production. Whether fractures are also increased in MGUS is unknown.
Materials and Methods: In a population-based retrospective cohort study, 488 Olmsted County, MN, residents with MGUS first diagnosed in 1960–1994 (52% men; mean age, 71.4 ± 12.8 years) were followed for 3901 person-years; follow-up was censored at progression to myeloma. The relative risk of fractures was assessed by standardized incidence ratios (SIRs), and risk factors were evaluated in proportional hazards models.
Results and Conclusions: Altogether, 200 patients experienced 385 fractures. Compared with expected rates in the community, statistically significant increases were seen for fractures at most axial sites, for example, vertebrae (SIR, 6.3; 95% CI, 5.2–7.5). There was a slight increase in hip (SIR, 1.6; 95% CI, 1.2–2.2) but not distal forearm fractures (SIR, 0.8; 95% CI, 0.4–1.5). The relative risk (SIR) of any axial fracture was 2.7 (95% CI, 2.3–3.1) compared with only 1.1 (95% CI, 0.9–1.4) for all limb fractures combined. In a multivariate analysis, the independent predictors of any subsequent fracture were age (hazard ratio [HR] per 10-year increase, 1.4; 95% CI, 1.2–1.6) and corticosteroid use (HR, 1.8; 95% CI, 1.2–2.6); greater weight at diagnosis (HR per 10 kg, 0.8; 95% CI, 0.8–0.9), and IgG monoclonal protein (HR, 0.7; 95% CI, 0.5–0.97) were protective. Baseline monoclonal protein level, a determinant of myeloma progression, did not predict fracture risk. Thus, the risk of axial, but not peripheral, fractures is increased among MGUS patients even before progression to myeloma. The pathophysiologic basis for this should be determined because elevated bone turnover, for example, might be treatable.
Isolation of a Human Homolog of Osteoclast Inhibitory Lectin That Inhibits the Formation and Function of Osteoclasts
Authors: Hu Yun Shan , Zhou Hong , Myers Damian , Quinn Julian MW , Atkins Gerald J , Ly Chi , Gange Christine , Kartsogiannis Vicky , Elliott Jan , Kostakis Panagiota , Zannettino Andrew CW , Cromer Brett , Mckinstry William J , Findlay David M , Gillespie Matthew T , Ng Kong Wah 
Published: April 2006

Abstract
Osteoclast inhibitory lectin (OCIL) is a newly recognized inhibitor of osteoclast formation. We identified a human homolog of OCIL and its gene, determined its regulation in human osteoblast cell lines, and established that it can inhibit murine and human osteoclast formation and resorption. OCIL shows promise as a new antiresorptive.
Introduction: Murine and rat osteoclast inhibitory lectins (mOCIL and rOCIL, respectively) are type II membrane C-type lectins expressed by osteoblasts and other extraskeletal tissues, with the extracellular domain of each, expressed as a recombinant protein, able to inhibit in vitro osteoclast formation.
Materials and Methods: We isolated the human homolog of OCIL (hOCIL) from a human fetal cDNA library that predicts a 191 amino acid type II membrane protein, with the 112 amino acid C-type lectin region in the extracellular domain having 53% identity with the C-type lectin sequences of rOCIL and mOCIL. The extracellular domain of hOCIL was expressed as a soluble recombinant protein in E. coli, and its biological effects were determined.
Results and Conclusions: The hOCIL gene is 25 kb in length, comprised of five exons, and is a member of a superfamily of natural killer (NK) cell receptors encoded by the NK gene complex located on chromosome 12. Human OCIL mRNA expression is upregulated by interleukin (IL)-1α and prostaglandin E2 (PGE2) in a time-dependent manner in human osteogenic sarcoma MG63 cells, but not by dexamethasone or 1,25 dihydroxyvitamin D3. Soluble recombinant hOCIL had biological effects comparable with recombinant mOCIL on human and murine osteoclastogenesis. In addition to its capacity to limit osteoclast formation, OCIL was also able to inhibit bone resorption by mature, giant-cell tumor-derived osteoclasts. Thus, a human homolog of OCIL exists that is highly conserved with mOCIL in its primary amino acid sequence (C-lectin domain), genomic structure, and activity to inhibit osteoclastogenesis.
A Genome-Screen of a Large Twin Cohort Reveals Linkage for Quantitative Ultrasound of the Calcaneus to 2q33–37 and 4q12–21
Authors: Wilson SG , Reed PW , Andrew T , Barber MJ , Lindersson M , Langdown M , Thompson D , Thompson E , Bailey M , Chiano M , Kleyn PW , Spector TD 
Published: April 2006

Abstract
A genome-wide screen was performed on a large cohort of dizygous twin pairs to identify regions of the genome that contain QTL for QUS of bone. Suggestive linkage of QUS parameters to 2q33–37 and 4q12–21 highlighted these regions as potentially important for studies of genes that regulate bone.
Introduction: The genetics of osteoporotic fracture is only partly explained by bone mineral density (BMD). Quantitative ultrasound (QUS) of the calcaneus can also be used for independent clinical assessment of osteoporotic fracture risk. Two specific indices are derived from this assessment: broadband ultrasound attenuation (BUA) and velocity of sound (VOS). Both parameters provide information on fracture risk; however, BUA has been studied more extensively and may be favored because it is thought to have a stronger predictive value for osteoporotic fracture and incorporates aspects of trabecular structure and bone quality as well as BMD. Studies of QUS in twins have shown that both derived parameters are under substantial genetic control, independent of BMD.
Materials and Methods: To identify regions of the genome that contain quantitative trait loci (QTL) for QUS of bone, we performed a genome-wide screen on a large cohort of dizygous twin pairs. Unselected female dizygous twins from 1067 pedigrees from the St Thomas' UK Adult Twin Registry were genome scanned (737 highly polymorphic microsatellite markers). Multipoint linkage analyses provided maximum evidence of linkage for BUA (LOD 2.1–5.1) to 2q33–37. Linkage for VOS (LOD 2.2–3.4) was maximal at 4q12–21. Potential evidence of linkage in the cohort indicated five other possible locations of QTL (LOD &gt;2.0) relevant to bone density or structure on chromosomes 1, 2, 13, 14, and X.
Results and Conclusions: This study has identified eight genomic locations with linkage of LOD &gt;2.0. This data should be of value in assisting researchers to localize genes that regulate bone mass and microstructure. These results should complement genome screens of BMD and bone structure and serve to enable further targeted positional candidate and positional cloning studies to advance our understanding of genetic control of bone quality and risk of fracture.
RANK Signaling Is Not Required for TNFα-Mediated Increase in CD11bhi Osteoclast Precursors but Is Essential for Mature Osteoclast Formation in TNFα-Mediated Inflammatory Arthritis
Authors: Li Ping , Schwarz Edward M , O'Keefe Regis J , Ma Lin , Boyce Brendan F , Xing Lianping 
Published: April 2006

Abstract
To address the controversy of whether TNFα can compensate for RANKL in osteoclastogenesis in vivo, we used a TNFα-induced animal model of inflammatory arthritis and blocked RANKL/RANK signaling. TNFα increased osteoclast precursors available for RANK-dependent osteoclastogenesis. RANK signaling is not required for the TNFα-stimulated increase in CD11bhi osteoclast precursors but is essential for mature osteoclast formation.
Introduction: Although critical roles of TNFα in inflammatory arthritis and RANKL in bone resorption have been firmly established, a central controversy remains about the extent to which TNFα can compensate for RANKL during osteoclastogenesis and the stage at which RANK signaling is required for osteoclastogenesis. Here, we used the human TNFα transgenic mouse model (TNF-Tg) of erosive arthritis to determine if there are both RANK-dependent and -independent stages of osteoclastogenesis in TNFα-induced erosive arthritis.
Materials and Methods: Osteoclastogenesis and osteoclast precursor (OCP) frequency were analyzed using histology, fluorescence-activated cell sorting (FACS), and cell culture from (1) TNF-Tg mice treated with the RANKL antagonist, RANK:Fc, or (2) TNF-Tg × RANK−/− mice generated by crossing TNF-Tg mice with RANK−/− mice.
Results: Treatment of TNF-Tg mice, which have increased OCPs in their spleens, with RANK:Fc dramatically reduced osteoclast numbers on the surface of their arthritic joints and within their bones, but did not decrease CD11bhi OCP numbers in their spleens. Long-term RANK:Fc administration alleviated joint erosion. Furthermore, TNF-Tg × RANK−/− mice had severe osteopetrosis, no osteoclasts, and no joint erosion, but increased CD11bhi precursor numbers that failed to form mature osteoclasts in vitro.
Conclusion: RANK signaling is essential for mature osteoclast formation in TNFα-mediated inflammatory arthritis but not for the TNFα-induced increase in CD11bhi OCP that subsequently can differentiate into osteoclasts in inflamed joints.
Biochemical Markers of Bone Metabolism and Prediction of Fracture in Elderly Women
Authors: Gerdhem Paul , Ivaska Kaisa K , Alatalo Sari L , Halleen Jussi M , Hellman Jukka , Isaksson Anders , Pettersson Kim , Väänänen H Kalervo , Åkesson Kristina , Obrant Karl J 
Published: April 2006

Abstract
We studied the ability of various markers of bone turnover to predict fracture in 1040 randomly recruited 75-year-old women. A total of 178 of the women sustained at least one fracture during follow-up (mean, 4.6 years). In elderly women, TRACP5b and urinary fragments of osteocalcin are promising new markers for prediction of fracture, in particular, vertebral fracture.
Introduction: Biochemical markers reflecting bone turnover may improve the prediction of fractures.
Materials and Methods: The ability of 10 markers of bone turnover to predict fracture in 1040 elderly women in the Malmö OPRA study was studied. Serum bone-specific alkaline phosphatase and four different forms of serum osteocalcin (S-OC) were analyzed as markers of bone formation and serum C-terminal cross-linking telopeptides of type I collagen (S-CTX), serum TRACP isoform 5b (S-TRACP5b) and urinary free deoxypyridinoline (U-DPD) as markers of bone resorption. Two novel assays for osteocalcin fragments in urine (U-OC) were analyzed. Areal BMD (aBMD) was measured by DXA in the femoral neck and lumbar spine.
Results: In total, 231 fractures were sustained by 178 of the women during a 3- to 6.5-year (mean, 4.6 years) follow-up period. When women with prospective fractures were compared with women without fractures, S-TRACP5b, S-CTX, one S-OC, and one U-OC were higher in women with a fracture of any type (all p &lt; 0.05), and all bone markers were higher in women with clinical vertebral fracture (all p &lt; 0.05). Markers were not significantly elevated in women with hip fracture. When women within the highest quartile of a bone marker were compared with all others, S-TRACP5b and one U-OC predicted the occurrence of a fracture of any type (odds ratio [OR]), 1.55 and 1.53; p &lt; 0.05). S-TRACP5b, the two U-OCs, and S-CTX predicted vertebral fracture (OR, 2.28, 2.75, 2.71, and 1.94, respectively; all p &lt; 0.05), and the predictive value remained significant for S-TRACP5b and the two U-OCs after adjusting for aBMD (OR, 2.02–2.25; p &lt; 0.05). Bone markers were not able to predict hip fracture.
Conclusion: These results show that biochemical markers of bone turnover can predict fracture, and in particular, fractures that engage trabecular bone. S-TRACP5b and U-OC are promising new markers for prediction of fracture.