Our long-range goal is to identify targets for new osteoporosis therapies that increase bone mass. Daily injection with parathyroid hormone (PTH) increases bone mass. In osteoblasts (OBs), cells that form bone tissue, PTH increases the expression of cyclooxygenase-2 (COX-2), which synthesizes the local lipid factors prostaglandins (PGs). It is likely that these PCs modulate the function of PTH. The predominant PG species produced by OBs is PGE2. We have found that PTH or PGE2 increases OB differentiation in the absence of COX-2 and treatment with PTH and PGE2 inhibits OB differentiation. On the other hand, PTH and PGE2 both increase the formation of osteoclasts (OCs), cells that resorb bone, in a processes regulated by OBs by expression of growth factors. When cultures are treated with PTH and PGE2 together, there is an increase in OC formation greater than PTH alone. In this proposal, we will study the mechanisms by which combination of PTH and PGE2 are inhibitory to OB differentiation, but enhance OC formation. We will measure the mRNA expression of growth factors associated OB differentiation and factors regulating OC formation following treatment of OBs with PTH, PGE2, and the combination. We will also measure activation of signal transduction pathways by PTH and PGE2, alone and in combination.
Osteoporosis is a disease that is characterized by low bone mass and increased risk of fracture. The only available therapy to increase bone mass is daily injection with parathyroid hormone, while other therapies inhibit bone loss. Our goal is to study the role of cyclooxygenase-2 derived, endogenous prostaglandins and parathyroid hormone in the regulation of osteoblast and osteoclast differentiation to identify new targets for improved therapies.
| Blackwell, Katherine A; Raisz, Lawrence G; Pilbeam, Carol C (2010) Prostaglandins in bone: bad cop, good cop? Trends Endocrinol Metab 21:294-301 |
| Blackwell, Katherine A; Hortschansky, Peter; Sanovic, Srdan et al. (2009) Bone morphogenetic protein 2 enhances PGE(2)-stimulated osteoclast formation in murine bone marrow cultures. Prostaglandins Other Lipid Mediat 90:76-80 |
