The mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by deficiencies in enzymes that degrade glycosaminoglycans (GAG). MPS VII is characterized by deficient beta-glucuronidase activity, leading to systemic accumulation of incompletely degraded chondroitin, heparan and dermatan sulfate GAGs. While disease is manifested in multiple organ systems, spine disease is particularly severe and includes morphological abnormalities in the intervertebral discs and vertebral bones, leading to spinal cord compression and kypho-scoliotic deformity. Currently there are no treatments, clinical or experimental, which correct spine disease in MPS VII. We have shown that MPS VII dogs have large, cartilaginous lesions in the vertebral bodies that compromise biomechanical stability of the intervertebral joint. These lesions are the result of failed conversion of cartilage to bone during postnatal development. The underlying molecular mechanisms that lead to this failure of endochondral ossification in MPS VII are unknown. During normal vertebral bone formation, cartilaginous rudiments form the template for subsequent ossification. The chondrocytes that populate these rudiments undergo distinct stages of differentiation, regulated by a highly orchestrated pattern of signaling pathways. Indian hedgehog (IHH) is a key regulator of chondrocyte differentiation. GAGs perform critical roles regulating the stability, distribution and binding of IHH during endochondral ossification. In pilot work we have shown that expression of key IHH pathway molecules is altered in the epiphyseal cartilage of MPS VII dogs compared to normals from early in postnatal development. Our overall hypothesis is that abnormal GAG accumulation in MPS VII disrupts chondrocyte proliferation and differentiation by interfering with the synthesis, stability, distribution and binding of IHH, preventing normal cartilage to bone conversion.
In Aim 1 we will investigate region-specific and age- dependent intra- and extracellular GAG accumulation patterns in developing MPS VII vertebrae, and establish how these patterns of GAG accumulation correspond to different stages of chondrocyte maturation.
In Aim 2 we will identify age-dependent differences in the expression and distribution of IHH and associated regulators of chondrocyte proliferation and hypertrophic differentiation between normal and MPS VII vertebrae.
In Aim 3 we will directly evaluate the cellular response to IHH, determine if exogenous enzyme administration can rescue the healthy phenotype of these cells, and evaluate the therapeutic potential of a small molecule IHH pathway agonist. The long-term goal of this work is to identify new therapeutic targets for MPS VII, for the other 11 enzyme deficiencies of the MPS family of disorders, and for other genetic musculoskeletal disorders that involve abnormal GAG synthesis or turnover.
The mucopolysaccharidoses (MPS) are genetic disorders characterized by systemic accumulation of poorly degraded glycosaminoglycans, and which have significant musculoskeletal manifestations. MPS VII patients have severe spine disease, including kypho-scoliotic deformity and spinal cord compression. We have shown that MPS VII spines have large cartilaginous lesions in the vertebrae, which represent failed cartilage to bone conversion during development. The goal of this study is to investigate the mechanisms of failed cartilage to bone conversion in MPS VII, and identify new therapeutic targets with relevance for all MPS disorders.