骨ルポ
ASBMR 2022 レポート
グリナズ アニワル（東京医科歯科大学大学院整形外科）
This was my first time attending a major international conference such as ASBMR and I felt very happy about it. Throughout the conference, I tried to listen to and see as many presentations and posters as possible, hoping to gain more useful knowledge. I feel sorry that I only attended this time online, and I hope to experience the academic atmosphere of such a large conference in the future.
紹介演題 [1]
Metagenomic Shotgun Sequencing of the Gut Microbiome in Two Cohort Studies and Associations with Skeletal Phenotypes and Cytokine 122 Concentrations
キーワード
bone remodelling，gut microbime，sequencing analysis
研究グループ
*Douglas Kiel, Xochitil Morgan, Curtis Huttenhower, Eric Orwoll, Paul Okoro, Shivani Sahni, Ramachandran S Vasan, Thomas Kuntz, Stanley Shaw, Yi-Hsiang Hsu, Mary Bouxsein.
- 1.Marcus Institute for Aging Research, Hebrew SeniorLife, United States
- 2.Harvard School of Public Health, United States
- 3.Oregon Health Sciences University, United States
- 4.Boston University School of Medicine, United States
- 5.Broad Institute of MIT
サマリー＆コメント
Disturbances in the gut microbiome have been linked to bone loss. Because of a lack of large human studies of the gut microbiome and skeletal health, we studied the gut microbi- ome and measures of volumetric BMD, microarchitecture, and strength as well as markers of inflammation in the Framingham 3rd Generation (n=558 men and women) and MrOS (n=776 men) cohorts. Both cohorts had stool sample metagenomic shotgun sequencing (Il- lumina 2x150 bp), with >=10 million reads/sample, and serum measures of RANKL, CRP (immunoturbidimetric assay or ELISA), and cytokines (IL-4, IL-17A, TNFα, IFNγ) per- formed using a Millipore multiplex human high sensitivity assay. HR-pQCT scans of the distal radius and tibia generated standard measures of vBMD, architecture and failure load. The Biobakery workflow was used for quality control (KneadData), taxonomic assignment (MetaPhlAn 3.0), and gene assignment (HUMAnN 2.0). Maaslin2.0 and MMUPHin were used to associate microbial species and genes with bone phenotypes and serum biomarkers, controlling for clinical covariates sex, age, race, BMI, a dietary quality index, number of medications, use of proton pump inhibitors or metformin, diabetes, and hospitalization in the past year.Mean age for the MrOS samples was 84.1+/-4.0 yrs) and for the Framingham sam- ples (55.4+/-8.8, 55% female). Analyses were conducted within cohort and then meta-ana- lyzed. Thirty-three taxa were significantly associated (q < 0.25) with cytokine abundance or bone phenotype, and 70% of these taxa were present in both cohorts. Of these microbial species, 10 were associated with TNFα, 5 with IL-4, 6 with trabecular measures, and 2 with tibial cortical measures. Species associated with multiple phenotypes included Lactobacil- lus fermentum (tCtTh, tFail Load, tTbInn vBMD) Clostridium_asparigiforme: (tFail Load, tTbInn vBMD, tTbvBMD), Victivallis vadensis (tTbvBMD, tTbInn vBMD), Dorea longi- catena (rTbN, TNFα), Clostridium_clostridioforme (rTbN, TNFα)). Positive and negative associations with phenotypes were roughly equal. The strongest positive association was between Flavonifractor plautii and rTbN. (See figure) This bacteria cleaves the C-ring of the flavonol, quercetin, that inhibits osteoclastogenesis. In conclusion, there were modest asso- ciations between gut microbial species and serum cytokines as well as skeletal phenotypes reinforcing observations in rodents that gut microbial species influence the skeleton through cytokine alterations.
My group has been doing research on the relationship between bacteria and bone mass in the intestine of rats. This excerpt gave me a lot of inspiration for how to conduct experiments in humans at a later stage, and gave me some new ideas for the experiments I am doing.
紹介演題 [2]
A BMP-controlled metabolic-epigenetic signaling cascade directs midfacial morphogenesis
キーワード
bone remodelling，BMPs，sequencing analysis
研究グループ
*Jingwen Yang , Yuji Mishina .
- School of Dentistry, University of Michigan, United States
サマリー＆コメント
Midline facial defects, which include facial skeletons, are one of the most common birth defects. During tissue morphogenesis, cell migration, growth and differentiation are controlled by strict genetic, signaling, and metabolic instructions. However, our understand- ing of the delicate integration between these functionally relevant mechanisms to regulate tissue development remains elusive. Here, we identify a novel BMP signaling controlled metabolic-epigenetic trans-cascade in regulating the behaviors of cranial neural crest cells (CNCCs) and midfacial morphogenesis. Using a transgenic mice model with constitutively activated Acvr1, a type I BMP receptor, in CNCCs (ca-Acvr1 mutant, hereafter), we found a small increase of BMP-Smad signaling causes midfacial defects, including midline facial cleft, bifurcation of nasal septum, and premaxilla hypoplasia in mice in association with sup- pression of glycolytic activities and thus its metabolites including lactate. Pharmacologic ac- tivation of glycolysis rescued facial defects, suggesting that glycolysis is a key for the facial defects. We further identified that glycolysis functions as a epigenetic regulator via histone lactylation in CNCCs. Histone lactylation, a newly identified epigenetic modification, stim- ulates gene expression. Levels of histone lactylation were decreased in the nasal processes of ca-Acvr1 mutants and these changes were restored by BMP-Smad signaling inhibitor LDN193189. We demonstrated that exogenous sodium lactate rescues the facial defects of ca-Acvr1 mutants in association with an increase of histone lactylation. To determine target genes of histone lactylation, we screened levels of genes critical for midfacial development and found that Pdgfra expression was most decreased in ca-Acvr1 mutants. It was reported that Pdgfra deletion in CNCCs causes a similar midfacial phenotype found in ca-Acvr1 mutants. Superimposing a constitutively activated Pdgfra allele (PdgfraK/+) into ca-Acvr1 mutants rescued the midfacial defects without restoring histone lactylation levels. We fur- ther identified high levels of histone lactylation at the promotor of Pdgfra by ChIP-qPCR in controls, which was reduced in ca-Acvr1 CNCC. These findings define a previously un- described axis wherein the BMP signaling controls a metabolic-epigenetic cascade to direct craniofacial morphogenesis, thus providing a novel conceptual framework for understanding the interaction between genetic and metabolic cues operative during embryogenesis.
When I was doing research on bacteria in the intestine, I discovered some pathways associated with BMP and In this excerpt, the authors mention findings about the BMP-Smad signaling pathway, which again inspired me to look into this signal next and see if it is useful.