Abstract
Osteoblasts undergo differentiation in response to various factors, including growth factors and steroids. Bone mass is diminished in androgen- and/or growth hormone (GH)-deficient patients. However the functional relationship between androgen and GH, and their combined effects on bone metabolism, remains unclear. Here we investigated the mutual effects of androgen and GH on osteoblastic marker expression using mouse myoblastic C2C12 and osteoblast-like MC3T3-E1 cells. Combined treatment with dihydrotestosterone (DHT) and GH enhanced BMP-2-induced expression of Runx2, ALP, and osteocalcin mRNA, compared with the individual treatments in C2C12 cells. Co-treatment with DHT and GH activated Smad1/5/8 phosphorylation, Id-1 transcription, and ALP activity induced by BMP-2 in C2C12 cells but not in MC3T3-E1 cells. The insulin-like growth factor (IGF-I) mRNA level was amplified by GH and BMP-2 treatment and was restored by co-treatment with DHT in C2C12 cells. The mRNA level of the IGF-I receptor was not significantly altered by GH or DHT, while it was increased by IGF-I. In addition, IGF-I treatment increased collagen-1 mRNA expression, whereas blockage of endogenous IGF-I activity using an anti-IGF-I antibody failed to suppress the effect of GH and DHT on BMP-2-induced Runx2 expression in C2C12 cells, suggesting that endogenous IGF-I was not substantially involved in the underlying GH actions. On the other hand, androgen receptor and GH receptor mRNA expression was suppressed by BMP-2 in both cell lines, implying the existence of a feedback action. Collectively the results showed that the combined effects of androgen and GH facilitated BMP-2-induced osteoblast differentiation at an early stage by upregulating BMP receptor signaling.
Highlights
Osteoblasts that have arisen from mesenchymal stem cell precursors undergo differentiation in response to various endocrine and autocrine/paracrine factors, including bone morphogenetic proteins (BMPs), growth hormone (GH), insulin-like growth factor-I (IGF-I), vitamin D, and steroids [1,2].J
Based on our pilot study using 10 to 10 M of DHT, a pharmacological dose, 10 M of DHT, the minimal dose enabling amplification of BMP‐induced signaling in C2C12 cells and that dose was was the minimal dose enabling amplification of BMP-induced signaling in C2C12 cells and that dose selected for the following study
For each result within a panel, the values with different superscript letters are significantly different at p < 0.05
Summary
Osteoblasts that have arisen from mesenchymal stem cell precursors undergo differentiation in response to various endocrine and autocrine/paracrine factors, including bone morphogenetic proteins (BMPs), growth hormone (GH), insulin-like growth factor-I (IGF-I), vitamin D, and steroids [1,2]. The functional interaction of androgen and the GH/IGF-I axis in osteoblast differentiation and bone formation remains to be elucidated. It is not clear whether androgen has an impact on bone metabolism via GH effects without IGF-I, through IGF-I action without GH, or independently of GH and IGF-I activity. We investigated the combined effects of androgen and GH on osteoblast marker expression in different stages of osteoblastic differentiation using two cell lines, with a focus on the interaction between BMP activity and pathways of the androgen receptor (AR) and the GH/IGF-I axis
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