Tgif1-deficiency impairs osteoclast differentiation through PP2A-mediated ERK1/2 dephosphorylation and attenuates bone loss in mice

Bone remodeling is a dynamic process regulated by the activities of osteoclasts and osteoblasts. Imbalances in this process can lead to osteoporosis, a condition characterized by low bone mass and increased fracture risk. The homeodomain protein TG-interacting factor 1 (Tgif1) has been previously identified as a key regulator of osteoblast function. Here, we investigate the cell-autonomous role of Tgif1 in osteoclasts. Our findings reveal that Tgif1 is expressed in osteoclast precursors, with its expression increasing during RANKL and M-CSF-induced differentiation. Deletion of Tgif1 in the osteoclast lineage impairs osteoclast differentiation and resorption capacity, reducing aging-related bone loss in mice in vivo. Mechanistically, Tgif1 restricts ERK1/2 dephosphorylation by suppressing protein phosphatase 2A (PP2A), an ERK1/2 phosphatase. Inhibition of PP2A restores impaired differentiation of Tgif1-deficient osteoclasts, confirming its involvement in this process. These findings establish Tgif1 as an important regulator of osteoclast differentiation, function, and bone resorption, offering new insights into molecular mechanisms controlling bone mass maintenance.