TRIM21 depletion negatively regulates osteoclastogenesis via association with JNK2 to reduce nucleation of NFATc1

Aberrant activation of osteoclast-mediated bone resorption has been observed in a series of skeletal diseases including osteoporosis and delayed or non-union bone fracture. Ubiquitination-mediated protein degradation has been revealed as an important mechanism for osteoporosis. Trim21 as an important E3 ubiquitin ligase, has been found to be critical for osteoclastogenesis. We have recently demonstrated that Trim21 is a crucial player in fine-tuning bone homeostasis, yet the underlying mechanism that affect bone resorption is largely unknown. Herein, we demonstrate that deletion of Trim21 led to decreased OC formation and activity accompanied by bone mass increase in mice. In addition, unbiased proteomics analysis identified that JNK2, was one of the key substance of Trim21. Mechanistically, we discovered that TRIM21 influences osteoclast differentiation by controlling the degradation of JNK2 via ubiquitin-dependent proteasomal or lysosomal degradation. Protein-protein interaction was further confirmed by immunofluorescence, leading to the modulation of NFATc1 nucleation. Our findings propose TRIM21 as a promising therapeutic target for osteoporosis.