Bone loss in survival motor neuron (Smn^−/−SMN2) genetic mouse model of spinal muscular atrophy

May 13, 2009The Journal of pathology

Bone loss in a genetic mouse model of spinal muscular atrophy

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Abstract

SMA mice exhibited an osteoporotic bone phenotype characterized by significant changes in bone structure.

MicroCT analysis showed a thin porous cortex and reduced trabecular bone in SMA mice compared to wild-type mice.
Histological examination revealed abundant activated osteoclasts on the sparse trabeculae and endosteal surface in SMA mice.
SMA mice had elevated serum TRAcP5b and urinary NTx levels, indicating increased bone resorption.
Markers for osteoblast differentiation were significantly reduced in SMA mice, while alkaline phosphatase levels remained unchanged.
Bone marrow cultures from SMA mice demonstrated a 54% increase in osteoclast formation and a 46% increase in bone resorption capacity.

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Spinal muscular atrophy (SMA) is characterized by degenerating lower motor neurons and an increased incidence of congenital bone fractures. Survival motor neuron (SMN) levels are significantly reduced due to deletions/mutations in the telomeric SMN1 gene in these patients. We utilized the Smn(-/-) SMN2 mouse model of SMA to determine the functional role for SMN in bone remodelling. microCT analysis of lumber vertebrae, tibia and femur bones from SMA mice revealed an osteoporotic bone phenotype. Histological analysis demonstrated a thin porous cortex of cortical bone and thin trabeculae at the proximal end of the growth plate in the vertebrae of SMA mice compared to wild-type mice. Histochemical staining of the vertebrae showed the presence of abundant activated osteoclasts on the sparse trabeculae and on the endosteal surface of the thin cortex in SMA mice. Histomorphometric analysis of vertebrae from SMA mice showed an increased number of osteoclasts. Serum TRAcP5b and urinary NTx levels were elevated, consistent with increased bone resorption in these mice. SMA mice showed a significant decrease in the levels of osteoblast differentiation markers, osteocalcin, osteopontin and osterix mRNA expression; however, there were no change in the levels of alkaline phosphatase expression compared to WT mice. SMA mouse bone marrow cultures revealed an increased rate of osteoclast formation (54%) and bone resorption capacity (46%) compared to WT mice. Pre-osteoclast cells from SMA mice showed constitutive up-regulation of RANK receptor signalling molecules critical for osteoclast differentiation. Our results implicate SMN function in bone remodelling and skeletal pathogenesis in SMA. Understanding basic mechanisms of SMN action in bone remodelling may uncover new therapeutic targets for preventing bone loss/fracture risk in SMA.

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Bone loss in survival motor neuron (Smn^−/−SMN2) genetic mouse model of spinal muscular atrophy

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