Alpha-1 antitrypsin inhibits RANKL-induced osteoclast formation and functions.
Osteoporosis is a global public health problem affecting more than 200 million people worldwide. We previously showed that treatment with alpha-1 antitrypsin (AAT), a multifunctional protein with anti-inflammatory properties, mitigated bone loss in an ovariectomized mouse model. However, the underlying mechanisms of the protective effect of AAT on bone tissue are largely unknown. In this study, we investigated the effect of AAT on osteoclast formation and functionin vitro. Our results showed that AAT dose-dependently inhibited the formation of RANKL (receptor activator of nuclear factor κB ligand) induced osteoclasts derived from mouse bone marrow macrophages/monocyte (BMM) lineage cells and the murine macrophage cell line, RAW 264.7 cells. In order to elucidate the possible mechanisms underlying this inhibition, we tested the effect of AAT on the gene expression of cell surface molecules, transcription factors, and cytokines associated with osteoclast formation. We showed that AAT inhibited M-CSF (macrophage colony-stimulating factor) induced cell surface RANK expression in osteoclast precursor cells. In addition, AAT inhibited RANKL-induced TNF-α production, cell surface CD9 expression, and dendritic cell-specific transmembrane protein (DC-STAMP) gene expression. Importantly, AAT treatment significantly inhibited osteoclast-associated mineral resorption. Together, these results uncovered new mechanisms for the protective effects of AAT and strongly support the notion that AAT has therapeutic potential for the treatment of osteoporosis.
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Mohammad Ahsanul
MA
Akbar
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
David
D
Nardo
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Mong-Jen
MJ
Chen
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Ahmed S
AS
Elshikha
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Rubina
R
Ahamed
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.|Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Egypt.
Eslam M
EM
Elsayed
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Claire
C
Bigot
Department of Orthodontics, College of Dentistry, University of Florida, Gainesville, Florida, USA.|Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, Florida, USA.
Lexie Shannon
LS
Holliday
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.
Sihong
S
Song
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010024:Osteoporosis / Q000188:drug therapy; D053245:RANK Ligand; D000067996:RAW 264.7 Cells; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
D016207:Cytokines; D053245:RANK Ligand; D000515:alpha 1-Antitrypsin; D016173:Macrophage Colony-Stimulating Factor
Mineral resorption; Osteoclastogenesis; Osteoporosis; RANK; c-Fos