The mucopolysaccharidoses (MPS) are a family of genetic, lysosomal storage diseases characterized by deficient activity of one of the 11 acid hydrolases responsible for glycosaminoglycan (GAG) degradation. In MPS, impaired hydrolase activity leads to incomplete digestion of GAGs and progressive accumulation of abnormal GAG fragments. This results in multi-systemic disease manifestations, including debilitating skeletal abnormalities that are particularly prevalent in the spine. While the defining pathological hallmark of MPS is abnormal GAG buildup, the molecular mechanisms that connect this accumulation to skeletal disease remain poorly understood. Thus, there are currently no effective therapeutics to treat skeletal manifestations of MPS. Elucidating the molecular mechanisms linking aberrant GAG accumulation to skeletal disease in MPS is a critical prerequisite to identifying new therapeutic targets and strategies. MPS VII is caused by a mutation in the ?-glucuronidase gene and presents with some of the most severe spinal manifestations including profound spinal instability, significantly diminishing quality of life and life expectancy. We previously demonstrated the presence of cartilaginous lesions in the vertebral bodies of a naturally-occurring canine model of MPS VII, which are also found in patients with MPS VII. These lesions, resulting from failed cartilage-to-bone conversion during development, contribute to progressive spinal deformity. In preliminary work, we identified the developmental window (between 9 and 14 days-of-age) when failed vertebral ossification first manifests in MPS VII dogs. Using whole transcriptome sequencing (RNA-Seq), we also found impaired activation of the bone morphogenetic protein (BMP) signaling pathway in this window. Growth factor signaling in the BMP pathway is critical to bone formation and is tightly regulated by GAGs. Thus, we hypothesize that accumulation of functionally abnormal GAGs in MPS VII results in aberrant extracellular sequestration of BMP growth factors, inhibiting BMP signaling and subsequent vertebral bone formation. Our overall objective is to elucidate the molecular mechanisms linking aberrant extracellular GAG accumulation to impaired BMP signaling and subsequent failed bone formation in MPS VII vertebral secondary ossification centers.
In Aim 1, we will confirm impaired activation of BMP signaling in MPS VII vertebral epiphyseal cartilage.
In Aim 2, we will define the nature of aberrant extracellular GAG accumulation and abnormal BMP growth factor binding in this tissue.
In Aim 3, we will establish decreased response to BMP growth factors of MPS VII epiphyseal chondrocytes as a result of aberrant extracellular GAG accumulation. Through elucidation of molecular mechanisms underlying MPS spine pathology, we will identify new targets for the development of therapeutics. More broadly, our findings will be applicable to other MPS subtypes and numerous other skeletal disorders that arise from abnormal GAG metabolism and provide critical, fundamental insights into GAG-mediated regulation of growth factor signaling in skeletal development.
The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders that affect children. Skeletal abnormalities, particularly of the spine, are prevalent, unresponsive to current treatments, and significantly diminish patient quality of life and life expectancy. The aim of this fellowship is to elucidate the molecular mechanisms of skeletal disease in MPS disorders, and specifically, to investigate links between abnormal glycosaminoglycan accumulation, impaired BMP signaling, and failed vertebral bone formation. Our long term goal is to identify new therapeutic targets to treat skeletal disease in MPS patients.
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