Bioactive analogs that simulate subsets of biological activities of 1 alpha,25(OH)(2)D-3 in osteoblasts

1 alpha ,25-Dihydroxyvitamin D-3 [1 alpha ,25(OH)(2)D-3] treatment of osteo blastic cells elicits a series of measurable responses that include both ra pid, membrane-initiated effects and longer-term nuclear receptor-mediated e ffects. Structural analogs have been identified and characterized that sele ctively activate subsets of these pathways. Two analogs from over 35 that h ave been tested were chosen for this comparison because they activate non-o verlapping response pathways, presumably representing either membrane-initi ated or nuclear receptor-initiated activities. Compound AT [25(OH)- 16ene-2 3yne-D-3] lacks the 1-hydroxyl essential for interacting with the nuclear r eceptor, but triggers Ca2+ influx through plasma membrane Ca2+ channels, au gments parathyroid hormone (PTH)-induced Ca2+ signals, dephosphorylates the matrix protein osteopontin (OPN), and along with PTH stimulates release of calcium from calvaria in organ culture. Compound BT [1 alpha ,24(OH)(2)-22 ene-24cyclopropyl-D-3] does not elicit any of the rapid responses or enhanc e PTH-induced bone resorption, but binds to the nuclear receptor for 1 alph a ,25(OH)(2)D-3 and increases steady state mRNA levels of both OPN and oste ocalcin over a 48 h period. Together, these two analogs recapitulate all of the known actions of 1 alpha ,25(OH)(2)D-3 on osteoblasts. Based on these findings, we conclude that Ca2+ release from bone stimulated by 1 alpha ,25 (OH)(2)D-3 and PTH is related to the rapid, membrane-initiated actions and is not likely to involve binding to the nuclear receptor for 1 alpha ,25(OH )(2)D-3. Longer term stimulation of bone formation by 1 alpha ,25(OH)(2)D-3 , however, appears to involve solely the nuclear receptor-mediated effects. These findings support our model of 1 alpha ,25(OH)(2)D-3 as a coupling fa ctor for bone resorption and formation during bone remodeling. (C) 2001 Els evier Science Inc. All rights reserved.