| First Author | Griffin AC 3rd | Year | 2012 |
| Journal | Mol Endocrinol | Volume | 26 |
| Issue | 10 | Pages | 1682-93 |
| PubMed ID | 22899855 | Mgi Jnum | J:318092 |
| Mgi Id | MGI:6858220 | Doi | 10.1210/me.2012-1033 |
| Citation | Griffin AC 3rd, et al. (2012) MKP-1 is essential for canonical vitamin D-induced signaling through nuclear import and regulates RANKL expression and function. Mol Endocrinol 26(10):1682-93 |
| abstractText | Vitamin D(3,) and its most active form, 1,25(OH)(2)D(3), are well known to stimulate osteoclastogenesis through stromal cell induction of the receptor activator of nuclear factor-kappaB ligand (RANKL). MAPK phosphatase-1 (MKP-1) is a phosphatase classically known to negatively regulate the innate immune response through dephosphorylation of p38, ERK, and c-Jun N-terminal kinase activity. This paper describes a new function of MKP-1 in permitting genomic 1,25(OH)(2)D(3) signaling and downstream osteoclastogenesis through RANKL. Initially, quantitative RT-PCR (qRT-PCR) and immunoblot analysis comparing bone marrow stromal cells (BMSC) revealed that 1,25(OH)(2)D(3)-induced vitamin D receptor (VDR), cytochrome P 45024a1, and RANKL mRNA expression and protein were significantly attenuated or absent in MKP-1(-/-) BMSC. Immunoblot analysis from cellular fractions of wild type and MKP-1(-/-) BMSC stimulated with 10(-7) m 1,25(OH)(2)D(3) revealed retinoid X receptor (RXR)alpha nuclear import was impaired in MKP-1(-/-) BMSC, whereas VDR import was not. Proximity ligation assays revealed that baseline VDR-RXRalpha heterodimer translocation was unchanged, yet 1,25(OH)(2)D(3)-induced nuclear translocation of VDR-RXRalpha heterodimers was reduced in MKP-1(-/-) BMSC. A functional consequence was observed as BMSC from MKP-1(-/-) mice treated with 1,25(OH)(2)D(3) and cocultured with RAW 264.7 cells had a 91% decrease in osteoclastogenesis and a 94.5% decrease in mineralized matrix resorption compared with wild-type cocultures (P < 0.01). These results reveal an unexpected, permissive role for MKP-1 in canonical 1,25(OH)(2)D(3) signaling via VDR-RXRalpha heterodimer nuclear import and downstream osteoclastogenesis through stromal cell RANKL expression. |
