Delayed Chondrocyte Differentiation and Altered Indian Hedgehog Signaling Contribute to Failed Vertebral Bone Formation in Mucopolysaccharidosis VII

Introduction Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disorder characterized by deficient activity of the enzyme b-glucuronidase, resulting in accumulation of poorly-degraded chondroitin, heparan, and dermatan sulfate glycosaminoglycans (GAGs). While MPS VII results in multi-systemic disease manifestations, skeletal abnormalities are particularly prevalent and significantly impact patient quality of life. In the spine, manifestations include accelerated disc degeneration, and malformed and misaligned vertebral bodies, leading to kyphoscoliotic deformity and spinal cord compression. There are currently no therapies that effectively treat spine disease in MPS VII. In previous studies, we demonstrated the presence of radiolucent, cartilaginous lesions at the vertebral epiphyses, which significantly compromise the structural and mechanical integrity of the intervertebral joint. We hypothesize that these lesions represent failed cartilage-to-bone conversion during post-natal development; the underlying pathological mechanisms responsible, however, remain unknown. During endochondral ossification, chondrocytes undergo distinct stages of differentiation, a process that is tightly regulated by a complex array of secreted growth factors. One such growth factor, Indian Hedgehog (IHH), performs crucial roles to regulate chondrocyte hypertrophic differentiation. The stability, distribution, and binding of IHH is regulated in part by GAGs, particularly heparan and chondroitin sulfates. The objective of this study was to investigate the mechanisms responsible for failed cartilageto-bone conversion in MPS VII, and specifically, to examine associations between abnormal GAG accumulation, abnormal chondrocyte differentiation, and altered IHH signaling in developing MPS VII vertebrae, using the naturally occurring canine model.