Progesterone is Extensively Metabolized in Osteoblasts: Implications for Progesterone Action on Bone

Abstract

The effect of progestogens on bone is controversial with some studies suggesting an anabolic action while others show no effect. Prereceptor metabolism via localized expression of specific enzymes may have major impact on progesterone action in bone and may explain some of the discrepancies between studies. We therefore investigated the metabolism of progesterone in primary cultures of human osteoblasts and MG-63 osteoblastic cells. Osteoblasts and MG-63 cells were incubated with 4- (14)C-progesterone tracer and 50 nM unlabeled progesterone, and magnitude and pattern of progesterone metabolism were determined by two-dimensional thin-layer chromatography. Conventional and Taqman real-time PCR analysis were used to assess expression of progesterone metabolizing enzymes. In both types of cells the two major metabolic products of progesterone were 20 alpha-dihydroprogesterone and 5 alpha-dihydroprogesterone, but conversion to 3 alpha, 5 alpha- and 3 beta, 5 alpha-tetrahydroprogesterone was also detected. This activity was concomitant with expression of mRNAs for the enzymes AKR1C1, 5 alpha-reductase type 1 and AKR1C2, and 3 beta-HSD type 1 and 3-hydroxysteroid epimerase. In MG-63 cells progesterone metabolism was largely mediated via 5 alpha-reductase. In primary osteoblasts progesterone metabolism was unaffected by treatment with dexamethasone or estradiol, but in MG-63 cells dexamethasone pretreatment increased 5 alpha-reductase activity. Progesterone is subject to extensive intracellular inactivation in human osteoblasts, with potential attenuation of local progesterone receptor responses. Conversely, osteoblasts have the capacity to convert progestogens to metabolites reported to have anabolic actions through the estrogen receptor.

The apoptotic effects of progesterone on breast cancer (MCF-7) and human osteosarcoma (MG-636) cells

“…Progesterone promotes osteocalcin gene transcription by stimulating the expression of c-fos and c-jun, resulting in osteoblast proliferation and differentiation [20]. Depending on their osteoblastic commitment, osteosarcoma cell lines respond to sex steroids [34]. In contrast to our findings and the results of studies supporting the inhibitory effects of progesterone on the proliferation and development of bone cells, there are reports suggesting that progesterone signaling is not essential for bone growth and turnover [19].…”

Nuclear Receptors in Bone Physiology and Diseases

“…Osteoblasts (292) and osteoclasts (369) express both PR-A and PR-B (550), suggesting that progesterone may exert its actions on both types of bone cells. Some in vitro studies showed that progesterone can be metabolized by osteoblasts (388) and that progesterone bounded PR exerts its anti-apoptotic action on osteoblast through inhibiting the activations of caspase-9 and -3 (514). Recent studies using conventional PR knockout (PRKO) mice (289) reported that PRKO mutants exhibited high bone mass with increased bone formation and reduced osteoclast surfaces (398).…”

Inhibitors of human 20α-hydroxysteroid dehydrogenase (AKR1C1)

“…AKR1C1 mRNA expression is highest in the lung, followed by the liver, testis, mammary gland, endometrium and brain. Recent reports show the expression of AKR1C1 in the kidney [8], adipose cells [9], skin [10], osteoblasts [11] and optic nerve head astrocytes [12]. Among the isoforms, AKR1C1 most efficiently reduces biologically active progesterone and 5␣-pregnan-3␣-ol-20-one into their corresponding 20␣-hydroxysteroids [7,13,14].…”