1Alpha,25-dihydroxyvitamin D3 inhibits GH-induced expression of SOCS-3 and CIS and prolongs growth hormone signaling via the Janus kinase (JAK2)/signal transducers and activators of transcription (STAT5) system in osteoblast-like cells.
Growth hormone (GH) and 1alpha,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) are regulators of bone growth and bone metabolism. In target cells, GH activates several signaling pathways, among them the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. GH mainly activates JAK2 and STAT5a and b. The effects of 1,25-(OH)(2)D(3) are mediated via a nuclear receptor, the vitamin D receptor, which, when bound by 1,25-(OH)(2)D(3), activates the transcription of target genes. In earlier studies (Morel, G., Chavassieux, P., Barenton, B., Dubois, P. M., Meunier, P. J., and Boivin, G. (1993) Cell Tissue Res. 273, 279-286) synergistic interaction between 1,25-(OH)(2)D(3) and GH regarding expression of osteoblastic markers has been described. The UMR 106 cell line is a rat osteosarcoma cell line with osteoblast-like properties. We have recently shown (Morales, O., Lindgren, U., and Haldosen, L. A. (2000) J. Bone Miner. Res. 15, 2284-2290) that UMR 106 cells express a GH-responsive JAK2/STAT5 signaling system. These cells also express the vitamin D receptor and respond to 1,25-(OH)(2)D(3). In the present study we have investigated whether 1,25-(OH)(2)D(3) influences GH signaling via the JAK2/STAT5 pathway in UMR 106 cells. We found that 1,25-(OH)(2)D(3) prolonged GH signaling via the JAK2/STAT5 pathway. Pretreatment of cells with 1,25-(OH)(2)D(3) was also necessary in order to detect GH-induced STAT5 transcriptional response. Furthermore, the pretreatment of cells with 1,25-(OH)(2)D(3) rendered to the cells the capacity to respond to repetitive GH-stimulation. In UMR 106 cells, GH induced the expression of the JAK/STAT negative regulatory proteins SOCS-3 and CIS. Interestingly, pretreatment with 1,25-(OH)(2)D(3) inhibited GH-induced expression of these proteins. From these results we propose that 1,25-(OH)(2)D(3) has an inhibitory effect on negative regulatory pathways acting on JAK2 and/or STAT5 in UMR 106 cells and that this, in all or partly, explains the effects of 1,25-(OH)(2)D(3) on GH-signaling via the JAK/STAT pathway.
Morales
Orlando
O
Department of Orthopedic Surgery, Karolinska Institutet, Huddinge Hospital, S-141 86 Huddinge, Sweden.
Faulds
Malin Hedengran
MH
Lindgren
Urban J
UJ
Haldosén
Lars-Arne
LA
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D013006:Growth Hormone / Q000378:metabolism / Q000502:physiology*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008894:Milk Proteins; D010006:Osteoblasts / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
D002117:Calcitriol; D004268:DNA-Binding Proteins; D013006:Growth Hormone; D017874:Immediate-Early Proteins; D008894:Milk Proteins; D011506:Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C491410:Socs3 protein, rat; C494094:Stat5a protein, rat