STARD3NL inhibits the osteogenic differentiation by inactivating the Wnt/β-catenin pathway via binding to Annexin A2 in osteoporosis.

Osteoporosis is one of the leading forms of systemic diseases related to bone metabolism in the world. STARD3 N-terminal like (STARD3NL) showed robust association with osteoporosis-related traits. Yet, the molecular functional mechanisms of STARD3NL in osteoblasts is still obscure. In this study, we demonstrated a high level of STARD3NL expression in the bone tissues from the patients with low bone mass and ovariectomized (OVX)-induced osteoporotic mice. We identified Stard3nl as a potent factor that negatively and positively regulates osteoblast differentiation and cell proliferation, respectively. Furthermore, inhibition of Stard3nl induced β-catenin gene expression and the nuclear translocation of β-catenin, as well as Wnt signalling activities, contributing to the activation of Wnt/β-catenin signalling. Mechanistic studies revealed that Stard3nl bound with Annexin A2 (Anxa2) to suppress β-catenin expression, resulting into the suppression of Wnt signalling and downstream osteogenic differentiation. Moreover, adeno-associated virus 9 (AAV9)-mediated silencing of Stard3nl reversed bone loss in OVX-induced osteoporotic mice by the injection into the knee joints. Collectively, our study revealed that Stard3nl suppressed osteogenesis via binding with Anxa2, resulting into the inactivation of Wnt signalling. It also highlights the preventive and therapeutic potential of STARD3NL as a specific and novel target for osteoporotic patients.