Steroid hormones including (1,25)-dihydroxyvitamin D3,
estrogens, and
glucocorticoids control bone development and homeostasis. We show here that the osteogenic
transcription factor Runx2 controls genes involved in
sterol/
steroid metabolism, including
Cyp11a1, Cyp39a1, Cyp51, Lss, and Dhcr7 in murine osteoprogenitor cells.
Cyp11a1 (P450scc) encodes an approximately 55-kDa mitochondrial
enzyme that catalyzes side-chain cleavage of
cholesterol and is rate limiting for
steroid hormone biosynthesis. Runx2 is coexpressed with
Cyp11a1 in osteoblasts as well as nonosseous cell types (e.g. testis and
breast cancer cells), suggesting a broad
biological role for Runx2 in
sterol/
steroid metabolism. Notably, osteoblasts and
breast cancer cells express an approximately 32-kDa truncated
isoform of
Cyp11a1 that is nonmitochondrial and localized in both the cytoplasm and the nucleus.
Chromatin immunoprecipitation analyses and gel shift assays show that Runx2 binds to the
Cyp11a1 gene promoter in osteoblasts, indicating that
Cyp11a1 is a direct target of Runx2. Specific
Cyp11a1 knockdown with
short hairpin RNA increases cell proliferation, indicating that
Cyp11a1 normally suppresses osteoblast proliferation. We conclude that Runx2 regulates
enzymes involved in
sterol/
steroid-related metabolic pathways and that activation of
Cyp11a1 by Runx2 may contribute to attenuation of osteoblast growth.