Abstract
Osteoporosis is a common disorder of bone remodeling, caused by the imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Recently, we reported that matrix metalloproteinase-9 (MMP-9)-dependent histone H3 proteolysis is a key event for proficient osteoclast formation. Although it has been reported that several MMP-9 inhibitors, such as tetracycline and its derivatives, show an inhibitory effect on osteoclastogenesis, the molecular mechanisms for this are not fully understood. Here we show that tetracycline analogs, especially tigecycline and minocycline, inhibit osteoclast formation by blocking MMP-9-mediated histone H3 tail cleavage. Our molecular docking approach found that tigecycline and minocycline are the most potent inhibitors of MMP-9. We also observed that both inhibitors significantly inhibited H3 tail cleavage by MMP-9 in vitro. These compounds inhibited receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast formation by blocking the NFATc1 signaling pathway. Furthermore, MMP-9-mediated H3 tail cleavage during osteoclast differentiation was selectively blocked by these compounds. Treatment with both tigecycline and minocycline rescued the osteoporotic phenotype induced by prednisolone in a zebrafish osteoporosis model. Our findings demonstrate that the tetracycline analogs suppress osteoclastogenesis via MMP-9-mediated H3 tail cleavage, and suggest that MMP-9 inhibition could offer a new strategy for the treatment of glucocorticoid-induced osteoporosis.
Highlights
Bone is a rigid but dynamic organ in which remodeling occurs continuously throughout life
We recently demonstrated that the matrix metalloproteinase matrix metalloproteinase-9 (MMP-9) is the key protease involved in histone H3 tail cleavage during osteoclast differentiation [6]
These two inhibitors were selected for our study, based on the molecular docking analysis. We determined whether these tetracycline analogs could inhibit MMP-9-mediated H3 tail cleavage during receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast differentiation
Summary
Bone is a rigid but dynamic organ in which remodeling occurs continuously throughout life. Glucocorticoids are widely used to suppress inflammation in a variety of chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel diseases, and are used as immunosuppressive agents, both for patients with malignancies and for organ transplant recipients; the glucocorticoids show diverse side effects [8] They exert effects on bone and muscle via several mechanisms, including a decrease in the number and function of osteoblasts and an increase in the life span and differentiation of osteoclasts. Third-generation tetracyclines, such as tigecycline, have been developed to overcome bacterial resistance to the earlier compounds [12] In addition to their antimicrobial activity, tetracyclines have been reported to block bone resorption [13,14]. Treatment with tigecycline and minocycline rescued the osteoporotic phenotype in a prednisolone-induced, osteoporosis zebrafish model
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