MicroRNA-29a represses osteoclast formation and protects against osteoporosis by regulating PCAF-mediated RANKL and CXCL12.

Abstract

Osteoporosis deteriorates bone mass and biomechanical strength, becoming a life-threatening cause to the elderly. MicroRNA is known to regulate tissue remodeling; however, its role in the development of osteoporosis remains elusive. In this study, we uncovered that silencing miR-29a expression decreased mineralized matrix production in osteogenic cells, whereas osteoclast differentiation and pit formation were upregulated in bone marrow macrophages as co-incubated with the osteogenic cells in transwell plates. In vivo, decreased miR-29a expression occurred in ovariectomy-mediated osteoporotic skeletons. Mice overexpressing miR-29a in osteoblasts driven by osteocalcin promoter (miR-29aTg/OCN) displayed higher bone mineral density, trabecular volume and mineral acquisition than wild-type mice. The estrogen deficiency-induced loss of bone mass, trabecular morphometry, mechanical properties, mineral accretion and osteogenesis of bone marrow mesenchymal cells were compromised in miR-29aTg/OCN mice. miR-29a overexpression also attenuated the estrogen loss-mediated excessive osteoclast surface histopathology, osteoclast formation of bone marrow macrophages, receptor activator nuclear factor-κ ligand (RANKL) and C-X-C motif chemokine ligand 12 (CXCL12) expression. Treatment with miR-29a precursor improved the ovariectomy-mediated skeletal deterioration and biomechanical property loss. Mechanistically, miR-29a inhibited RANKL secretion in osteoblasts through binding to 3'-UTR of RANKL. It also suppressed the histone acetyltransferase PCAF-mediated acetylation of lysine 27 in histone 3 (H3K27ac) and decreased the H3K27ac enrichment in CXCL12 promoters. Taken together, miR-29a signaling in osteogenic cells protects bone tissue from osteoporosis through repressing osteoclast regulators RANKL and CXCL12 to reduce osteoclastogenic differentiation. Arrays of analyses shed new light on the miR-29a regulation of crosstalk between osteogenic and osteoclastogenic cells. We also highlight that increasing miR-29a function in osteoblasts is beneficial for bone anabolism to fend off estrogen deficiency-induced excessive osteoclastic resorption and osteoporosis.

• Authors: Wei-Shiung Lian, Jih-Yang Ko, Yu-Shan Chen, Huei-Jing Ke, Chin-Kuei Hsieh, Chung-Wen Kuo, Shao-Yu Wang, Bo-Wun Huang, Jung-Ge Tseng, Feng-Sheng Wang
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 10 Pg. 705 (09 23 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 31543513 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CXCL12
• Cxcl12 protein, mouse
• MIRN29a microRNA, human
• MicroRNAs
• RANK Ligand
• Tnfsf11 protein, mouse
• p300-CBP Transcription Factors
• p300-CBP-associated factor

Topics

• Animals
• Biomechanical Phenomena
• Bone and Bones (cytology, metabolism)
• Cell Communication (physiology)
• Cell Differentiation (physiology)
• Chemokine CXCL12 (genetics)
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• MicroRNAs (genetics, metabolism)
• Osteoclasts (cytology, metabolism)
• Osteoporosis (genetics)
• Ovariectomy
• RANK Ligand (genetics, metabolism)
• p300-CBP Transcription Factors (genetics, metabolism)