microRNAs (miRNAs) play critical regulatory roles in multiple types of skeletal cells. Despite the accumulating evidence for miRNAs' involvement in multiple processes of skeletal development and homeostasis, specific roles of individual miRNAs in vivo are largely unknown. miR-17-92 miRNAs are abundantly expressed in stem/progenitor cells and are implicated in their maintenance by promoting proliferation and suppressing differentiation. miR-17-92 cluster miRNAs are so far the only miRNAs whose genetic mutations have been demonstrated to cause human congenital skeletal diseases; duplications of the miR-17-92 gene cause macrocephaly and digit abnormalities, whereas its heterozygous deletions result in Feingold syndrome II that is characterized by macrocephaly and brachysyndactyly. In addition, we have also found that miR-17- 92 miRNAs negatively regulate osteoblast differentiation and bone mass in mice. However, the mechanisms by which miR-17-92 miRNAs regulate skeletal development and bone homeostasis are unknown. Because miR-17-92 miRNAs are predicted to target more than 2,000 genes, identifying critical molecular mechanisms is a challenge. On the other hand, it is presumed that physiologically important miRNA-RNA interactions are evolutionarily selected to control certain biological processes and pathways, as miR-17-92 miRNAs have been reported to regulate several signaling pathways in a cellular context dependent manner. Based on these findings, we hypothesize that miR-17-92 miRNAs regulate key signaling pathways in skeletal stem/progenitor cells to control their proliferation and differentiation, and thus regulate skeleta development and bone homeostasis. To test this hypothesis, we will first generate mouse models to define the role of miR-17-92 miRNAs in skeletal development and postnatal bone homeostasis at the tissue and cellular levels in vivo. We will then dissect molecular mechanisms that mediate miR-17-92 miRNAs' action at the levels of miRNA-RNA interaction, gene expression, and signaling pathways. This project will define the role and mechanisms of action of miR-17-92 miRNAs in skeletal stem/progenitor cells during skeletal development and bone homeostasis and will provide the basis for developing new therapeutic strategies for miR-17-92-related diseases and for common skeletal diseases such as osteoporosis.

Public Health Relevance

Mutations of the miR-17-92 miRNA gene cause human congenital skeletal defects. However it is not known how miR-17-92 miRNAs regulate skeletal development and bone homeostasis. This project aims to define the role and mechanism of action of miR-17-92 miRNAs and to provide the basis for developing new therapeutic strategies for miR-17-92-related diseases and common skeletal diseases such as osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056645-07
Application #
9241351
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2010-04-01
Project End
2021-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
7
Fiscal Year
2017
Total Cost
$330,883
Indirect Cost
$132,883
Name
Massachusetts General Hospital
Department
Type
Domestic Higher Education
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Mirzamohammadi, Fatemeh; Kozlova, Anastasia; Papaioannou, Garyfallia et al. (2018) Distinct molecular pathways mediate Mycn and Myc-regulated miR-17-92 microRNA action in Feingold syndrome mouse models. Nat Commun 9:1352
Suzuki, Hiroshi I; Spengler, Ryan M; Grigelioniene, Giedre et al. (2018) Deconvolution of seed and RNA-binding protein crosstalk in RNAi-based functional genomics. Nat Genet 50:657-661
Kobayashi, Tatsuya; Kozlova, Anastasia (2018) Lin28a overexpression reveals the role of Erk signaling in articular cartilage development. Development 145:
Mirzamohammadi, Fatemeh; Papaioannou, Garyfallia; Inloes, Jennifer B et al. (2016) Polycomb repressive complex 2 regulates skeletal growth by suppressing Wnt and TGF-? signalling. Nat Commun 7:12047
Kong, Li; Zhao, Yun-Peng; Tian, Qing-Yun et al. (2016) Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone-related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor. FASEB J 30:2741-54
Papaioannou, Garyfallia; Mirzamohammadi, Fatemeh; Kobayashi, Tatsuya (2016) Ras signaling regulates osteoprogenitor cell proliferation and bone formation. Cell Death Dis 7:e2405
Kobayashi, T; Papaioannou, G; Mirzamohammadi, F et al. (2015) Early postnatal ablation of the microRNA-processing enzyme, Drosha, causes chondrocyte death and impairs the structural integrity of the articular cartilage. Osteoarthritis Cartilage 23:1214-20
Papaioannou, Garyfallia; Mirzamohammadi, Fatemeh; Lisse, Thomas S et al. (2015) MicroRNA-140 Provides Robustness to the Regulation of Hypertrophic Chondrocyte Differentiation by the PTHrP-HDAC4 Pathway. J Bone Miner Res 30:1044-52
Papaioannou, Garyfallia; Mirzamohammadi, Fatemeh; Kobayashi, Tatsuya (2014) MicroRNAs involved in bone formation. Cell Mol Life Sci 71:4747-61
Mirzamohammadi, Fatemeh; Papaioannou, Garyfallia; Kobayashi, Tatsuya (2014) MicroRNAs in cartilage development, homeostasis, and disease. Curr Osteoporos Rep 12:410-9

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