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Congenital Bone Fractures in Spinal Muscular Atrophy: Functional Role for SMN Protein in Bone Remodeling

Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston

Kathryn J. Swoboda, MD

Department of Neurology, University of Utah School of Medicine, Salt Lake City

Susan T. Iannaccone, MD, FAAN

Department of Child Neurology, Children's Medical Center, University of Texas Southwestern Medical Center, Dallas

William L. Ries, DDS, PhD

Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston

Bernard L. Maria, MD, MBA

Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston

Sakamuri V. Reddy, PhD

Charles P. Darby Children's Research Institute, Medical University of South Carolina, Charleston, reddysv{at}musc.edu

Spinal muscular atrophy is the second most common fatal childhood disorder. Core clinical features include muscle weakness caused by degenerating lower motor neurons and a high incidence of bone fractures and hypercalcemia. Fractures further compromise quality of life by progression of joint contractures or additional loss of motor function. Recent observations suggest that bone disease in spinal muscular atrophy may not be attributed entirely to lower motor neuron degeneration. The presence of the spinal muscular atrophy disease-determining survival motor neuron gene (SMN), SMN expression, and differential splicing in bone-resorbing osteoclasts was recently discovered. Its ubiquitous expression and the differential expression of splice variants suggest that SMN has specific roles in bone cell function. SMN protein also interacts with osteoclast stimulatory factor. Mouse models of human spinal muscular atrophy disease suggest a potential role of SMN protein in skeletal development. Dual energy x-ray absorptiometry analysis demonstrated a substantial decrease in total bone area and poorly developed caudal vertebra in the mouse model. These mice also had pelvic bone fractures. Studies delineating SMN signaling mechanisms and gene transcription in a cell-specific manner will provide important molecular insights into the pathogenesis of bone disease in children with spinal muscular atrophy. Moreover, understanding bone remodeling in spinal muscular atrophy may lead to novel therapeutic approaches to enhance skeletal health and quality of life. This article reviews the skeletal complications associated with spinal muscular atrophy and describes a functional role for SMN protein in osteoclast development and bone resorption activity.

Key Words: spinal muscular atrophy • bone fractures • SMN protein • osteoclasts

References

• Swoboda KJ, Prior TW, Scott CB, et al. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol. 2005;57(5):704-712.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Hausmanowa-Petrusewicz I., Vrbová G. Spinal muscular atrophy: a delayed development hypothesis. Neuroreport. 2005;16(7): 657-661.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Lefebvre S., Burglen L., Reboullet S., et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-165.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Le TT, Pham LT, Butchbach ME, et al. SMN7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet. 2005;14(6):845-857.[Abstract/Free Full Text]
• Lorson CL, Strasswimmer J., Yao JM, et al. SMN oligomerization defect correlates with spinal muscular atrophy severity. Nat Genet. 1998;19(1):63-66.[Web of Science][Medline] [Order article via Infotrieve]
• Lorson CL, Hahnen E., Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A. 1999;96(11): 6307-6311.[Abstract/Free Full Text]
• Felderhoff-Mueser U., Grohmann K., Harder A., et al. Severe spinal muscular atrophy variant associated with congenital bone fractures. J Child Neurol. 2002;17(9):718-721.[Abstract/Free Full Text]
• Kelly TE, Amoroso K., Ferre M., Blanco J., Allinson P., Prior TW Spinal muscular atrophy variant with congenital fractures. Am J Med Genet. 1999;87(1):65-68.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Khawaja K., Houlsby WT, Watson S., Bushby K., Cheetham T. Hypercalcaemia in infancy: a presenting feature of spinal muscular atrophy. Arch Dis Child. 2004;89(4):384-385.[Abstract/Free Full Text]
• Kinali M., Banks LM, Mercuri E., Manzur AY, Muntoni F. Bone mineral density in a paediatric spinal muscular atrophy population. Neuropediatrics. 2004;35(6):325-328.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Jiang SD, Jiang LS, Dai LY Mechanisms of osteoporosis in spinal cord injury. Clin Endocrinol (Oxf). 2006;65(5):555-565.[CrossRef][Medline] [Order article via Infotrieve]
• Geusens P., Reid D. Newer drug treatments: their effects on fracture prevention. Best Pract Res Clin Rheumatol. 2005;19(6): 983-989.[CrossRef][Medline] [Order article via Infotrieve]
• Bergin A., Kim G., Price DL, Sisodia SS, Lee MK, Rabin BA Identification and characterization of a mouse homologue of the spinal muscular atrophy-determining gene, survival motor neuron Gene. 1997;204(1-2):47-53 [published correction appears in Gene. 1998;213(1-2):227].[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Schrank B., Götz R., Gunnersen JM, et al. Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc Natl Acad Sci U S A. 1997;94(18):9920-9925.[Abstract/Free Full Text]
• Hsieh-Li HM, Chang JG, Jong YJ, et al. A mouse model for spinal muscular atrophy. Nat Genet. 2000;24(1):66-70.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Monani UR, Sendtner M., Coovert DD, et al. The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy. Hum Mol Genet. 2000;9(3): 333-339.[Abstract/Free Full Text]
• Kurihara N., Menaa C., Maeda H., Haile DJ, Reddy SV Osteoclast-stimulating factor interacts with the spinal muscular atrophy gene product to stimulate osteoclast formation. J Biol Chem. 2001; 276(44):41035-41039.[Abstract/Free Full Text]
• Ross FP, Teitelbaum SL vß3 and macrophage colony-stimulating factor: partners in osteoclast biology. Immunol Rev. 2005;208(1): 88-105.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Reddy SV Regulatory mechanisms operative in osteoclasts. Crit Rev Eukaryot Gene Expr. 2004;14(4):255-270.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Reddy S., Devlin R., Menaa C., et al. Isolation and characterization of a cDNA clone encoding a novel peptide (OSF) that enhances osteoclast formation and bone resorption. J Cell Physiol. 1998; 177(4):636-645.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Szymkiewicz I., Destaing O., Jurdic P., Dikic I. SH3P2 in complex with Cbl and Src. FEBS Lett. 2004;565(1-3):33-38.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Sanjay A., Houghton A., Neff L., et al. Cbl associates with Pyk2 and Src to regulate Src kinase activity, vß3 integrin-mediated signaling, cell adhesion, and osteoclast motility. J Cell Biol. 2001; 152(1):181-195.[Abstract/Free Full Text]
• Iwahashi H., Eguchi Y., Yasuhara N., Hanafusa T., Matsuzawa Y., Tsujimoto Y. Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy. Nature. 1997;390(6658):413-417.[CrossRef][Medline] [Order article via Infotrieve]
• Lefebvre S., Burlet P., Liu Q., et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997;16(3):265-269.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Zou J., Barahmand-pour F., Blackburn ML, Matsui Y., Chansky HA, Yang L. Survival motor neuron (SMN) protein interacts with transcription corepressor mSin3A. J Biol Chem. 2004;279(15):14922-14928.[Abstract/Free Full Text]
• Liu Q., Fischer U., Wang F., Dreyfuss G. The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell. 1997;90(6):1013-1021.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Giesemann T., Rathke-Hartlieb S., Rothkegel M., et al. A role for polyproline motifs in the spinal muscular atrophy protein SMN: profilins bind to and colocalize with SMN in nuclear gems. J Biol Chem. 1999;274(53):37908-37914.[Abstract/Free Full Text]
• Strasswimmer J., Lorson CL, Breiding DE, et al. Identification of survival motor neuron as a transcriptional activator–binding protein. Hum Mol Genet. 1999;8(7):1219-1226.[Abstract/Free Full Text]
• Williams BY, Hamilton SL, Sarkar HK The survival motor neuron protein interacts with the transactivator FUSE binding protein from human fetal brain. FEBS Lett. 2000;470(2):207-210.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Gangwani L., Mikrut M., Theroux S., Sharma M., Davis RJ Spinal muscular atrophy disrupts the interaction of ZPR1 with the SMN protein. Nat Cell Biol. 2001;3(4):376-383.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Young PJ, Day PM, Zhou J., Androphy EJ, Morris GE, Lorson CL A direct interaction between the survival motor neuron protein and p53 and its relationship to spinal muscular atrophy. J Biol Chem. 2002;277(4):2852-2859.[Abstract/Free Full Text]

Journal of Child Neurology, Vol. 22, No. 8, 967-973 (2007)
DOI: 10.1177/0883073807305664


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