Androgens suppress osteoclast formation induced by RANKL and macrophage-colony stimulating factor

Area of Science:

• Endocrinology
• Bone Biology
• Cell Biology

Background:

• Androgen deficiency in males increases osteoclastic bone resorption and decreases bone mineral density.
• Osteoclast formation is regulated by receptor activator of NF-kB ligand (RANKL) and macrophage-colony stimulating factor.

Purpose of the Study:

• To investigate the ability of 5 alpha-dihydrotestosterone to suppress osteoclast formation in vitro.
• To explore the role of androgens and estrogen (E2) in regulating osteoclast differentiation.

Main Methods:

• In vitro studies using bone marrow monocytes and RAW264.7 cell line.
• Assessment of osteoclast differentiation induced by RANKL and macrophage-colony stimulating factor.
• Analysis of androgen and E2 effects on cellular signaling pathways, including c-Jun and activator protein-1 (AP-1).

Main Results:

• 5 alpha-dihydrotestosterone suppressed osteoclast differentiation from bone marrow monocytes in both sham-operated and orchidectomized mice.
• Androgen deficiency increased osteoclast precursors and their responsiveness to androgens.
• Both 5 alpha-dihydrotestosterone and E2 effectively suppressed osteoclast formation.
• In RAW264.7 cells, 5 alpha-dihydrotestosterone blocked RANKL-induced osteoclast formation by inhibiting c-Jun N-terminal kinase activation and reducing c-Jun expression, thereby reducing AP-1 DNA binding and transcriptional activity.

Conclusions:

• Both androgens and estrogen can directly suppress osteoclast formation on osteoclast precursors.
• This suppression occurs independently of stromal cells.
• The mechanism involves blocking essential transcription factors like c-Jun, crucial for osteoclast differentiation.