Autotaxin negatively regulates parathyroid hormone-induced osteogenesis through autocrine inhibition of β-catenin signaling

Autotaxin (ATX/ENPP2) is a lysophospholipase D responsible for lysophosphatidic acid (LPA) production from lysophosphatidylcholine in biological fluids. LPA controls bone metabolism through interplay between specific LPA receptors. However, because Enpp2 deletion causes embryonic lethality, ATX functions within the osteoblast cell lineage and its contributions to bone growth remain undefined. This study shows that expression of Enpp2 is upregulated during osteoblastogenesis and reveales Enpp2 as a target gene of the cAMP signaling pathway. The bone anabolic molecule parathyroid hormone 1–34 fragment (PTH) further increases Enpp2 expression in osteoblasts. Enpp2 expression was significantly higher in bone of transgenic Col1-PPR mice expressing constitutively active PTHR1. PTH treatment elevated circulating ATX levels in mice and hypoparathyroidism patients under PTH therapy. Conditional deletion of Enpp2 in osteoblastic cells (ObDATX) enhanced increased trabecular bone mass and osteoblast activity in response to PTH. Transcriptomic analysis revealed upregulation of bone- and Wnt-related genes in ObDATX mice treated with PTH. In vitro , pharmacological ATX inhibition stimulated osteogenesis, and both pharmacological inhibition and genetic deletion of ATX induced spontaneous accumulation of active β-catenin and transcription of Wnt/β-catenin target genes. These results reveals that ATX as a new negative feed-back regulator of PTH1-34-induced osteogenesis by blocking the Wnt/β-catenin canonical pathway. These data provide insight to a better understanding of mechanism of bone response to PTH and offer a new therapeutic strategy to enhance bone anabolism.