Natural products such as plant lectins have not been extensively surveyed for their potential as anabolic agents. Wlodarski (1991) observed that the lectin Concanavalin A (ConA) has chondrogenic and osteogenic activity following local injection over the mouse tibia. To gain more insight into the mechanism of ConA in bone, we investigated and quantitated the effects of ConA injected locally over the mouse calvaria in vivo. ConA was injected subcutaneously over the calvaria of mice at 2, 10, and 20 microg per injection, four times a day, for three consecutive days. By day fourteen, a layer of new woven bone 30 microm thick had been laid down on the periosteal surface, resulting in a 36% increase in calvarial thickness (as compared with 2% in vehicle-treated controls). ConA also increased periosteal width and osteoblast surface in a dose-dependent manner. Concurrent administration of indomethacin (30 microg) with ConA (20 microg), four times a day for 3 days, strongly inhibited new bone formation. With a single injection of ConA (80 microg) over the calvaria, osteoclastic bone resorption and proliferation of osteoblast precursors and periosteum increased at day four, but showed a decrease at later times (14 and 28 days after injection). Except at the earliest time, there was little evidence of osteoclastic bone resorption. New bone width increased linearly over 28 days. In summary, ConA induced new bone formation in a pattern comparable with that of aFGF and bFGF, potent stimulators of calvarial bone formation (Dunstan, 1993), and this osteogenic effect was caused by an indomethacin-sensitive pathway.