Tumor production of endothelin-1 (ET-1) mediates new bone formation associated with osteoblastic metastases through the endothelin A receptor (ETA). However, the mechanisms by which this occurs and the role of ET-1 in normal bone remodeling is unknown, and will be the topic of this investigation.
Aim 1 : ET-1 stimulates new bone growth but whether this occurs by increased proliferation of osteoprogenitor cells, enhanced differentiation to mature osteoblasts or by inhibition of osteoblast apoptosis will be determined.
Aim 2 : The transactivation of the epidermal growth factor receptor by ET-1 will be tested to establish 1) if this is an important signaling pathway responsible for stimulating osteoblast activity and 2) whether estradiol modulates this effect.
Aim 3 : The roles of Wnt5a and Dickkopf homolog 1 autocrine signaling, Beta-catenin and the calcium-sensitive signaling pathways in ET-1 stimulation of osteoblast activity will be tested.
Aim 4 : The Cre-loxP system was utilized to make an osteoblast-specific knockout mouse with a targeted deletion of ETA. Since sex steroids modulate the effects of ETA blockade, eugonadal and castrated mice will be analyzed for gross anatomic and histologic bone developmental abnormalities. ? ?
| Clines, Gregory A; Mohammad, Khalid S; Grunda, Jessica M et al. (2011) Regulation of postnatal trabecular bone formation by the osteoblast endothelin A receptor. J Bone Miner Res 26:2523-36 |
| Clines, Gregory A; Mohammad, Khalid S; Bao, Yongde et al. (2007) Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. Mol Endocrinol 21:486-98 |
