Our results further illustrated that the REGγ-20S proteasome directly degrades the E3 ligase TRAF6, indicating that the alternative ubiquitin-independent proteasome pathway is an extremely attractive protein degradation mechanism and that the regulation of the REGγ-20S proteasome/TRAF6 pathway could be a potential strategy for osteoporosis treatment. Here, TRAF6 is linked to osteoporosis.