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

Oct 13, 2025FASEB journal : official publication of the Federation of American Societies for Experimental Biology

Loss of SMN May Disrupt Bone-Building and Bone-Breaking Cell Interaction Through IGF1-Akt-OPG Pathway in Spinal Muscular Atrophy

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Abstract

SMA mice exhibited significant bone mass reduction characterized by impaired bone formation and increased bone resorption.

Osteogenesis was impaired, while osteoclastogenesis was increased in SMA mice.
In vitro findings showed suppressed osteoclast differentiation from bone marrow-derived macrophages in SMA mice, contrasting with in vivo results.
Osteoclast hyperactivity was linked to decreased osteoblast-derived (OPG), driven by local (IGF1) deficiency.
SMN protein loss led to IGF1 downregulation, which inhibited the PI3K-Akt signaling pathway and reduced OPG expression.
Exogenous OPG administration mitigated osteoclast differentiation and promoted osteoblast function, partially restoring bone formation.

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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 (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 (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.

Key numbers

60%

Decrease in

Measured in 3-month-old mice vs. control mice.

Not specified

Increase in RANKL/ Ratio

Observed in mice compared to controls.

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

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