Loss of SMN Impairs Osteoblast-Osteoclast Coupling via IGF1-Akt-OPG Axis in Spinal Muscular Atrophy

Recent advancements in therapeutics have extended lifespan and improved neurodevelopmental outcomes in spinal muscular atrophy (SMA) patients, particularly with severe phenotypes. However, most patients fail to achieve normal motor function. Although structural bone defects and increased fracture susceptibility have been reported in both SMA patients and mouse models, the role of survival motor neuron (SMN) protein in bone homeostasis and therapeutic targets remains incompletely understood. To investigate the function of SMN in bone metabolism, a mild SMA mouse model and Smn1 conditional knockout mice in the myeloid lineage and mature osteoclasts were utilized. Bone architecture was assessed using micro-computed tomography (micro-CT), histological staining, and immunohistochemistry. RNA sequencing was performed to explore molecular mechanisms underlying skeletal defects. Primary bone marrow mesenchymal stem cells (BMSCs) and bone marrow-derived macrophages (BMMs) were differentiated into osteoblasts and osteoclasts, respectively, and co-cultured to evaluate SMN-dependent regulation of osteoblast-osteoclast interactions. The therapeutic potential of exogenous osteoprotegerin (OPG) administration was further assessed. SMA mice exhibited significant bone mass reduction, characterized by impaired osteogenesis and increased osteoclastogenesis. However, in vitro experiments revealed suppressed osteoclast differentiation in BMMs from SMA mice, which was inconsistent with in vivo findings. Co-culture studies demonstrated that osteoclast hyperactivity in SMA mice resulted from decreased osteoblast-derived OPG, induced by local insulin-like growth factor 1 (IGF1) deficiency. Mechanistically, SMN depletion led to IGF1 downregulation, thereby suppressing PI3K-Akt signaling, reducing OPG expression, and ultimately disrupting osteoblast-osteoclast coupling. Administration of exogenous OPG effectively mitigated osteoclast differentiation and resorptive activity, indirectly promoting osteoblast function and partially restoring bone formation. These findings reveal that SMN protein loss caused IGF1 deficiency that inhibited the PI3K-Akt signaling pathway, leading to downregulation of OPG expression and disrupted osteoblast-osteoclast coupling. This study highlights the therapeutic potential of targeting OPG in SMA to alleviate skeletal complications and improve patient outcomes.