Plectin promotes bone formation via phase separation and sequestering annexin A2

Osteoporosis constitutes an emergent threat to human health, which partially caused by impaired osteoblast differentiation. Liquid-liquid phase separation (LLPS) is a cytophysiological process that regulates osteoblast differentiation. The plakin family, ubiquitously expressed in osteoblasts, interacts with multiple proteins and may mediate phase separation. However, limited reports exist regarding the involvement of the plakin family phase separation and osteoblast differentiation. In this study, we demonstrated that plectin (Plec), a plakin family member, enhances osteoblast differentiation and bone formation via its phase separation. This process is mediated by plectin's intrinsically disordered region (IDR). Mechanistically, plectin promotes osteoblast differentiation by sequestering annexin A2 (Anxa2), an osteoblast differentiation promoter, through phase separation. Furthermore, the functional amino acid region (aa 1967–2185) of plectin exhibited therapeutic effect in mice with osteoporosis. Our findings reveal a novel regulatory mechanism by which cytoskeletal linker proteins govern osteoblast differentiation and propose a potential therapeutic strategy for osteoporosis.