POLR2A blocks osteoclastic bone resorption and protects against osteoporosis by interacting with CREB1.

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 0050222 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4652 (Electronic) Linking ISSN: 00219541 NLM ISO Abbreviation: J Cell Physiol Subsets: MEDLINE

Publication: New York, NY : Wiley-Liss
Original Publication: Philadelphia, Wistar Institute of Anatomy and Biology.

Bone Resorption/*prevention & control ; Cyclic AMP Response Element-Binding Protein/*biosynthesis ; DNA-Directed RNA Polymerases/*metabolism ; Osteoporosis/*prevention & control; Animals ; Bone Resorption/pathology ; DNA-Directed RNA Polymerases/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Osteoclasts/cytology ; Osteogenesis/physiology ; Osteoporosis/pathology ; RNA Interference ; RNA, Small Interfering/genetics ; Signal Transduction/physiology ; Transcription, Genetic/genetics

Bone-resorbing osteoclasts significantly contribute to osteoporosis, and understanding the mechanisms of osteoclastogenesis is crucial for developing new drugs to treat diseases associated with bone loss. Here, we report that POLR2A is upregulated during osteoclastogenesis. Functional analyses showed that the inhibition of POLR2A decreased osteoclastogenesis, whereas the overexpression of POLR2A had completely opposite effects in vitro. Notably, the osteoclast-specific deletion of POLR2A blocks bone resorption in vivo. Furthermore, POLR2A loss-of-function suppresses estrogen deficiency-induced bone resorption. Mechanistically, POLR2A regulates the assembly of CREB1 on the regulatory elements of its target genes. Collectively, using genetic, pharmacological, and disease mouse models, we have identified a previously undescribed protein that interacts with CREB1 to regulate osteoclastic bone resorption.
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Keywords: CREB1; POLR2A; bone resorption; osteoclastogenesis; osteoporosis

0 (Creb1 protein, mouse)
0 (Cyclic AMP Response Element-Binding Protein)
0 (RNA, Small Interfering)
EC 2.7.7.6 (DNA-Directed RNA Polymerases)

Date Created: 20210217 Date Completed: 20211014 Latest Revision: 20211014

20221213

10.1002/jcp.30220

33595106