EFFECT OF ENZYME REPLACEMENT THERAPY ON BONE-FORMATION IN A FELINE MODEL OF MUCOPOLYSACCHARIDOSIS TYPE-VI

A range of skeletal abnormalities are evident in mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) including short stature and dysostosis multiplex, resulting from a deficiency in the lysosomal hy drolase N-acetylgalactosamine-4-sulphatase (4S). In this article, bone pathology was assessed in a feline model of MPS VI to evaluate the ef ficacy of enzyme replacement therapy (ERT) as a treatment modality for this genetic disorder. Osteopenia is clearly evident in MPS VI animal s, with bone mineral volume (BV/TV) falling well below that of normal animals (4.39% vs. 20.11%, respectively). Trabecular bone architecture was also affected in MPS VI with fewer, thinner, and more widely spac ed trabeculae apparent. Bone formation rate (BFR/BS) was also lower in MPS VI animals than controls (0.0011 mm(3)/mm(2) per day vs. 0.008 mm (3)/mm(2) per day, respectively). Vertebral and tibial bone length in MPS VI animals progressively fell behind normal values with increasing age, as did cortical bone thickness. Vertebral body shape was also al tered. ERT with recombinant human 4S (rh4S) resulted in a vertebral BV /TV of 8.23% in animals treated with an intravenous enzyme dose of 1 m g/kg and a BV/TV of 14.33% in animals treated with a dose of 5 mg/kg. BFR/BS also increased to 0.0034 mm(3)/mm(2) per day in animals treated with enzyme doses of either 1.0 or 5.0 mg/kg rh4S. All other affected histomorphometric parameters also improved with ERT to a level interm ediate between MPS VI untreated animals and normals. However, individu al animals treated with 0.2 mg/kg rh4S intravenously or 1.0 mg/kg rh4S administered subcutaneously did not exhibit an improvement over untre ated MPS VI animals. Vertebral and tibial bone lengths, tibial cortica l bone thickness, and vertebral body shape also responded to ERT, with a trend away from the untreated group. Thus, ERT had a positive effec t on bone development in MPS VI animals that was dependent upon the do se of enzyme administered and the route of administration. (C) 1997 by Elsevier Science Inc. All rights reserved.