Abstract
Osteoporosis is a global public health problem affecting more than 200 million people worldwide. We previously showed that treatment with α-1 antitrypsin (AAT), a multifunctional protein with antiinflammatory 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 function in vitro. Our results showed that AAT dose-dependently inhibited the formation of receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclasts derived from mouse bone marrow macrophage/monocyte (BMM) lineage cells and the RAW 264.7 murine macrophage cell line. 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 macrophage colony-stimulating factor (M-CSF)-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 uncover new mechanisms for the protective effects of AAT and strongly support the notion that AAT has therapeutic potential for the treatment of osteoporosis.
Highlights
Bone homeostasis is maintained by the mutual function of bone-resorbing hematopoietic lineage–derived osteoclasts (OCs) and mesenchymal stem cell–derived bone-forming osteoblasts [1]
The late-stage osteoclast precursor (OCP) cells were further stimulated with RANKL and macrophage colony–stimulating factor (M-CSF) for an additional 3 d
These results indicate that AAT inhibited the formation of RANKL-induced mature multinuclear OCs
Summary
Bone homeostasis is maintained by the mutual function of bone-resorbing hematopoietic lineage–derived osteoclasts (OCs) and mesenchymal stem cell–derived bone-forming osteoblasts [1]. The balance between osteoclasts and osteoblasts is important for normal skeletal formation and function. Osteoclast formation is a normal aspect of skeletal morphogenesis and remodeling; disproportionate osteoclast proliferation and activation can lead to excessive bone resorption. This can subsequently lead to chronic systemic bone diseases such as osteoporosis, which is a serious public health problem affecting an estimated 34 million Americans and causing 2 million fractures annually [3,4]. Strategies to inhibit excessive osteoclast formation and/or function have proven to have therapeutic usefulness for the treatment of osteoporosis [1]. The use of currently available drugs is limited due to their side effects, including osteonecrosis of the jaw, which can be caused by nitrogen-containing bisphosphonates, the most commonly used antiresorptive drugs, and denosumab, a monoclonal antibody inhibitor of RANKL [1,5]
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