Control of lipid metabolism in chondrocytes is critical for skeletal growth

Remarkably, no skeletal phenotype is observed in mice lacking Ppp1r15b in committed Osx⁺ osteoprogenitors (Ppp1r15bOsx) and Dmp1⁺ mature osteoblasts and osteocytes (Ppp1r15bDmp1), indicating that its role is limited to regulation of chondrogenesis, not osteogenic differentiation. Mechanistically, PPP1R15B deletion increases eIF2α phosphorylation, which in turn enhances lipogenic gene expression by suppressing Leptin. This effect was reversed in Ppp1r15bPrx1 mice by reconstitution with wildtype PPP1R15B, but not with a mutant form incapable of eIF2α dephosphorylation.

Exogenous expression of Leptin also reversed skeletal abnormalities in these mice. Collectively, these findings reveal a previously unrecognized role for PPP1R15B in cartilage development through its regulation of lipid metabolism.