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Selective Estrogen Receptor Modulators Suppress Hif1α Protein Accumulation in Mouse Osteoclasts
Mayu Morita1, Yuiko Sato2,3, Ryotaro Iwasaki1
1Division of Oral and Maxillofacial surgery, Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582, Japan.
Abstract:
Anti-bone resorptive drugs such as bisphosphonates, the anti-RANKL antibody (denosumab), or selective estrogen receptor modulators (SERMs) have been developed to treat osteoporosis. Mechanisms underlying activity of bisphosphonates or denosumab in this context are understood, while it is less clear how SERMs like tamoxifen, raloxifene, or bazedoxifene inhibit bone resorption. Recently, accumulation of hypoxia inducible factor 1 alpha (Hif1α) in osteoclasts was shown to be suppressed by estrogen in normal cells. In addition, osteoclast activation and decreased bone mass seen in estrogen-deficient conditions was found to require Hif1α. Here, we used western blot analysis of cultured osteoclast precursor cells to show that tamoxifen, raloxifene, or bazedoxifene all suppress Hif1α protein accumulation. The effects of each SERM on osteoclast differentiation differed in vitro. Our results suggest that interventions such as the SERMs evaluated here could be useful to inhibit Hif1α and osteoclast activity under estrogen-deficient conditions.
Insights
Selective estrogen receptor modulators (SERMs) like tamoxifen, raloxifene, and bazedoxifene suppress hypoxia-inducible factor 1 alpha (Hif1α) accumulation in osteoclasts. This suggests SERMs may inhibit bone resorption and osteoclast activity in estrogen deficiency.
Area of Science:
- Endocrinology
- Bone Biology
- Pharmacology
Background:
- Osteoporosis treatment involves anti-resorptive drugs like bisphosphonates, denosumab, and selective estrogen receptor modulators (SERMs).
- The mechanism by which SERMs inhibit bone resorption is less understood compared to other drug classes.
- Estrogen normally suppresses hypoxia-inducible factor 1 alpha (Hif1α) in osteoclasts, and Hif1α is required for osteoclast activation in estrogen deficiency.
Purpose of the Study:
- To investigate the effect of SERMs (tamoxifen, raloxifene, bazedoxifene) on Hif1α accumulation in osteoclasts.
- To explore the potential of SERMs in managing bone resorption under estrogen-deficient conditions.
Main Methods:
- Western blot analysis was performed on cultured osteoclast precursor cells.
- The impact of tamoxifen, raloxifene, and bazedoxifene on Hif1α protein levels was assessed.
Main Results:
- Tamoxifen, raloxifene, and bazedoxifene were all found to suppress Hif1α protein accumulation.
- Differential effects of each SERM on osteoclast differentiation were observed in vitro.
Conclusions:
- SERMs effectively inhibit Hif1α accumulation in osteoclasts.
- The evaluated SERMs show potential for inhibiting Hif1α and osteoclast activity in estrogen-deficient states, offering a therapeutic avenue for osteoporosis.
