Association study of semaphorin 7a (sema7a) polymorphisms with bone mineral density and fracture risk in postmenopausal Korean women

Koh, Jung‐Min; Oh, Bermseok; Lee, Jong Yong; Lee, Jong-Keuk; Kimm, Kuchan; Kim, Ghi Su; Park, Byung Lae; Cheong, Hyun Sub; Shin, Hyoung Doo; Hong, Jung Min; Kim, Sang Woo; Park, Eui Kyun; Kim, Shin‐Yoon

doi:10.1007/s10038-005-0331-z

Cited by 52 publications

(50 citation statements)

References 23 publications

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“…In an in vitro model of periodontal ligament remodeling in tension, where bone formation is stimulated and osteoclastic resorption is inhibited, Sema7A was repressed, consistent with a resorptive role for this semaphorin [71]. Furthermore, human Sema7A single nucleotide polymorphisms are associated with decreased bone mass and increased fracture risk [72]. Thus, Runx2-mediated increase in Sema7A in mesenchymal progenitors and osteoblasts likely contributes to their increased ability to induce osteoclastogenesis.…”

Section: Resultsmentioning

confidence: 99%

Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells

et al. 2011

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Summary We profiled the global gene expression of a bone marrow-derived mesenchymal pluripotent cell line in response to Runx2 expression. Besides osteoblast differentiation, Runx2 promoted the osteoclastogenesis of co-cultured splenocytes. This was attributable to the upregulation of many novel osteoclastogenic genes and the downregulation of anti-osteoclastogenic genes. Introduction In addition to being a master regulator for osteoblast differentiation, Runx2 controls osteoblast-driven osteoclastogenesis. Previous studies profiling gene expression during osteoblast differentiation had limited focus on Runx2 or paid little attention to its role in mediating osteoblast-driven osteoclastogenesis. Methods ST2/Rx2dox, a bone marrow-derived mesenchymal pluripotent cell line that expresses Runx2 in response to Doxycycline (Dox), was used to profile Runx2-induced gene expression changes. Runx2-induced osteoblast differentiation was assessed based on alkaline phosphatase staining and expression of classical marker genes. Osteoclastogenic potential was evaluated by TRAP staining of osteoclasts that differentiated from primary murine splenocytes co-cultured with the ST2/Rx2dox cells. The BeadChip™ platform (Illumina) was used to interrogate genome-wide expression changes in ST2/Rx2dox cultures after treatment with Dox or vehicle for 24 or 48 h. Expression of selected genes was also measured by RT-qPCR. Results Dox-mediated Runx2 induction in ST2 cells stimulated their own differentiation along the osteoblast lineage and the differentiation of co-cultured splenocytes into osteoclasts. The latter was attributable to the stimulation of osteoclastogenic genes such as Sema7a, Ltc4s, Efnb1, Apcdd1, and Tnc as well as the inhibition of anti-osteoclastogenic genes such as Tnfrsf11b (OPG), Sema3a, Slco2b1, Ogn, Clec2d (Ocil), Il1rn, and Rspo2. Conclusion Direct control of osteoblast differentiation and concomitant indirect control of osteoclast differentiation, both through the activity of Runx2 in pre-osteoblasts, constitute a novel mechanism of coordination with a potential crucial role in coupling bone formation and resorption.

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Section: Resultsmentioning

confidence: 99%

Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells

et al. 2011

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“…These findings indicated for the first time the possible involvement of Sema-7A in bone cell differentiation [Delorme et al, 2005]. Recently, it was also shown that polymorphisms of the Sema-7A gene were associated with the bone mineral density of the lumbar spine and the femoral neck [Koh et al, 2006].…”

Section: Introductionmentioning

confidence: 89%

“…However, recent studies have shown that many of the semaphorins and their receptors are also expressed by osteoblasts and osteoclasts. Furthermore, they were found to play an important role in the development and remodeling of bone through the regulation of osteoblast or osteoclast differentiation [Harper et al, 2001;Delorme et al, 2005;Koh et al, 2006;Tamagnone and Giordano, 2006]. As is the case for the other secreted chemorepellents for the guidance of neuronal axons and neurons, slits have similar molecular structure and func- Results were standardized using GAPDH as a housekeeping gene and then expressed as relative mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Osteoblast Differentiation by Slit2 in Osteoblastic Cells

Sun

Dai

Tang

et al. 2008

Cells Tissues Organs

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Background/Aims: There is an urgent need to identify the molecular factors involved in osteoblast proliferation and differentiation in order to improve bone formation and treat bone disease. Recent studies demonstrate that many ‘axon guidance’ molecules play important roles in the development and remodeling of bone through their actions regulating osteoblast or osteoclast differentiation. The expressions and roles in bone tissue of the neuron guidance molecules slit and robo have not been reported previously. The objective of the current study is to investigate the expression and the roles of slit and robo in osteoblastic cells. Methods: The mRNAs slit2 and robo were detected in primary cell lines during their osteoblastic differentiation. The role of slit2 was studied using the recombinant proteins slit2 and hemagglutinin (HA)-roboN by transfecting the 293 cells. Results: The data indicated that the mRNAs of slit2, robo1 and robo2 were expressed during the osteoblastic differentiation of rat osteoblasts (calvarial osteoblasts derived from newborn rats), the nontransformed preosteogenic cell line MC3T3-E1, rat marrow stromal cells and the murine mesenchymal progenitor cell line C3H10T1/2. The exogenous slit2 protein inhibited the differentiation of rat osteoblasts and MC3T3-E1. Furthermore, the osteoblastic differentiation was improved when the endogenous slits were antagonized by recombinant HA-roboN, which is the extracellular domain of the rat robo1 protein. The inhibition of slit2 in osteogenic differentiation was independent of the RhoA/ROCK pathway. Conclusion: Slit2 plays a role in regulating in vitro osteoblast differentiation. This has opened a new avenue to understand the molecular events involved in the osteoblastic differentiation.

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“…SEMA7A polymorphisms are associated with abnormal bone mineral density in Korean women (72). During acute lung injury, TGFB1 can increase endothelial and epithelial permeability (73)(74)(75), and the inhibition of TGFB1 can diminish lung injury (66,(76)(77)(78).…”

Section: Discussionmentioning

confidence: 99%

Integrative Assessment of Chlorine-Induced Acute Lung Injury in Mice

Leikauf

Pope-Varsalona

Concel

et al. 2012

Am J Respir Cell Mol Biol

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The genetic basis for the underlying individual susceptibility to chlorine-induced acute lung injury is unknown. To uncover the genetic basis and pathophysiological processes that could provide additional homeostatic capacities during lung injury, 40 inbred murine strains were exposed to chlorine, and haplotype association mapping was performed. The identified single-nucleotide polymorphism (SNP) associations were evaluated through transcriptomic and metabolomic profiling. Using > 10% allelic frequency and > 10% phenotype explained as threshold criteria, promoter SNPs that could eliminate putative transcriptional factor recognition sites in candidate genes were assessed by determining transcript levels through microarray and reverse real-time PCR during chlorine exposure. The mean survival time varied by approximately 5-fold among strains, and SNP associations were identified for 13 candidate genes on chromosomes 1, 4, 5, 9, and 15. Microarrays revealed several differentially enriched pathways, including protein transport (decreased more in the sensitive C57BLKS/J lung) and protein catabolic process (increased more in the resistant C57BL/10J lung). Lung metabolomic profiling revealed 95 of the 280 metabolites measured were altered by chlorine exposure, and included alanine, which decreased more in the C57BLKS/J than in the C57BL/10J strain, and glutamine, which increased more in the C57BL/10J than in the C57BLKS/J strain. Genetic associations from haplotype mapping were strengthened by an integrated assessment using transcriptomic and metabolomic profiling. The leading candidate genes associated with increased susceptibility to acute lung injury in mice included Klf4, Sema7a, Tns1, Aacs, and a gene that encodes an amino acid carrier, Slc38a4.

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Association study of semaphorin 7a (sema7a) polymorphisms with bone mineral density and fracture risk in postmenopausal Korean women

Cited by 52 publications

References 23 publications

Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells

Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells

Regulation of Osteoblast Differentiation by Slit2 in Osteoblastic Cells

Integrative Assessment of Chlorine-Induced Acute Lung Injury in Mice

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