期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 124, 期 6, 页码 2736-2749出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI73072
关键词
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资金
- National Institute of Arthritis and Musculoskeletal
- Skin Diseases of the NIH [R01-AR057759]
- MESA
- MESA SHARe [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169]
- National Heart, Lung, and Blood Institute (NHLBI) [RR-024156]
- NHLBI [NO2-HL-6-4278]
- NIH
- National Cancer Institute (NCI)
- National Human Genome Research Institute (NHGRI)
- NHLBI
- National Institute on Drug Abuse (NIDA)
- National Institute of Mental Health (NIMH)
- National Institute of Neurological Disorders and Stroke (NINDS)
- NCI\SAIC-Frederick Inc. (SAIC-F) - National Disease Research Interchange [10XS170]
- Roswell Park Cancer Institute [10XS171]
- Science Care Inc. [X10S172]
- Laboratory, Data Analysis, and Coordinating Center (LDACC) - Broad Institute Inc. [HHSN268201000029C]
- SAIC-F subcontract with Van Andel Institute [10ST1035]
- SAIC-F [HHSN261200800001E]
- University of Miami [DA006227]
- University of Geneva [MH090941]
- University of Chicago [MH090951, MH09037]
- University of North Carolina at Chapel Hill [MH090936]
- Harvard University [MH090948]
- [R01HL071739]
Patient bone mineral density (BMD) predicts the likelihood of osteoporotic fracture. While substantial progress has been made toward elucidating the genetic determinants of BMD, our understanding of the factors involved remains incomplete. Here, using a systems genetics approach in the mouse, we predicted that bicaudal C homolog 1 (Bicc1), which encodes an RNA-binding protein, is responsible for a BMD quantitative trait locus (QTL) located on murine chromosome 10. Consistent with this prediction, mice heterozygous for a null allele of Bicc1 had low BMD. We used a coexpression network-based approach to determine how Biccl influences BMD. Based on this analysis, we inferred that Biccl was involved in osteoblast differentiation and that polycystic kidney disease 2 (Pkd2) was a downstream target of Bicc1. Knock down of Bicc1 and Pkd2 impaired osteoblastogenesis, and Bicc1 deficiency-dependent osteoblast defects were rescued by Pkd2 overexpression. Last, in 2 human BMD genome-wide association (GWAS) meta-analyses, we identified SNPs in BICC1 and PKD2 that were associated with BMD. These results, in both mice and humans, identify Biccl as a genetic determinant of osteoblastogenesis and BMD and suggest that it does so by regulating Pkd2 transcript levels.
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