A plate of rapidly dividing chondrocytes—cartilage-forming cells—controls elongation within the bone (cartilage of mouse tibia stained orange here). Previous work has shown that the versatile molecule gp130 influences bone formation, but the data have not yielded a clean story. In the 2 February Journal of Clinical Investigation, Natalie Sims et al. clear the air.

Credit: Reprinted with permission of JCI

Previous studies had found that gp130-knockout mice ramp up production of osteoclasts, bone-resorbing cells. But the picture quickly becomes more complicated. In cell culture, for instance, antibodies that neutralize gp130 also increase osteoclast formation.

gp130 dimers can activate two signaling pathways: the STAT-1/3 transcription pathway and the SHP-2/Ras/MAPK pathway. To dissect the influence of each of these pathways, Sims et al. took advantage of mice containing mutations that knocked out each pathway independently. The investigators found that STAT-1/3-mediated proliferation of chondrocytes and bone-forming osteoblasts. The SHP-2/Ras/MAPK pathway inhibited formation of bone-eating osteoclasts.

The authors speculate that the output could depend on gp130 binding partners. For instance, the cytokine IL-6, previously implicated in arthritis, was found to stimulate osteoblast generation through gp130/STAT-1/3 signaling.