ORM1 mediates osteoblast/osteoclast crosstalk in adolescent idiopathic scoliosis via RANKL/OPG ratio alteration

Adolescent idiopathic scoliosis (AIS), a complex early-onset three-dimensional spinal deformity, remains etiologically ambiguous despite extensive ongoing investigations. Currently, braces and surgeries are primary treatments of AIS, which come with inherent risks and costs. Therefore, there is an urgent need for biotherapeutic targets for AIS. Using human specimens obtained from the clinic, we discovered that ORM1 was expressed in AIS bone tissues. Also, immune cells were found to interact with osteoclasts through the LTB-LTBR pathway, resulting in elevated ORM1 expression, proliferation promotion and differentiation of monocytes/osteoclasts. Protein analysis showed that in ORM1-positive AIS patient-derived osteoblasts, there was an increased expression of RANKL, decreased expression of OPG, and an increased RANKL/OPG ratio. Furthermore, osteoclasts overexpressing ORM1 promoted their own differentiation while inhibiting osteoblast proliferation and function. ORM1 knockdown osteoclasts co-cultured with osteoblasts, along with the addition of leptin, significantly inhibited osteoclast differentiation while promoting osteoblast proliferation and function-related protein expression. In conclusion, ORM1 acts as a detrimental factor in the pathogenesis of Adolescent Idiopathic Scoliosis (AIS) by promoting osteoclast differentiation and inhibiting both the proliferation and function of osteoblasts. This suggests that ORM1 may represent a valuable therapeutic target for AIS.