Osteonectin or SPARC is one of the most abundant non-collagen matrix components in bone. This "matricellular" protein regulates extracellular matrix assembly and maturation in addition to modulating cell behavior. Mice lacking osteonectin develop severe low turnover osteopenia, and in vitro studies of osteonectin-null osteoblastic cells showed that osteonectin supports osteoblast formation, maturation and survival. The present studies demonstrate that osteonectin-null osteoblastic cells have increased expression of Notch 1, a well documented regulator of cell fate in multiple systems. Further, osteonectin-null cells are more plastic and less committed to osteoblastic differentiation, able to pursue adipogenic differentiation given the appropriate signals. Notch 1 transcripts are down regulated by inducers of cAMP in both wild type and osteonectin-null osteoblasts, suggesting that the mutant osteoblasts may have a defect in generation of cAMP in response to stimuli. Indeed, many bone anabolic agents signal through increased cAMP. Wild type and osteonectin-null osteoblasts generated comparable amounts of cAMP in response to forskolin, a direct stimulator of adenylyl cyclase. However, the ability of osteonectin-null osteoblasts to generate cAMP in response to cholera toxin, a direct stimulator of G_s, was attenuated. These data imply that osteonectin-null osteoblasts have decreased coupling of G_s to adenylyl cyclase. Since osteonectin promotes G protein coupling to an effector, our studies support the concept that low turnover osteopenia can result from reducing G protein coupled receptor activity.