Type I mucopolysaccharidosis (MPS I) IntroductionType I mucopolysaccharidosis (MPS I) is one of the most frequent lysosomal storage disorders (LSDs) and is due to the inherited deficiency of ␣-L-iduronidase (IDUA) activity, which results in the accumulation of its unprocessed substrates (glycosaminoglycans; GAGs) in many organs. 1 The disorder is systemic and clinically heterogeneous. Clinical manifestations include skeletal dysplasia, joint stiffness, visual and auditory defects, cardiac insufficiency, hepatosplenomegaly, and mental retardation. The clinical spectrum ranges from the severe Hurler syndrome (MPS I-H) to the attenuated Scheie syndrome. Mental retardation is distinctive only of MPS I-H, which is fatal in childhood if untreated, thus representing the variant with the most urgent need for new therapies. Enzyme replacement therapy (ie, parenteral administration of exogenous enzyme that can be internalized by tissue cells via the mannosium-6-phosphate receptor) is recommended only for MPS I patients without primary neurologic disease, due to the inability of the enzyme to efficiently cross the blood-brain barrier; moreover, neutralizing antibodies can attenuate its efficacy. 2 When performed at early ages, hematopoietic stem cell (HSC) transplantation (HCT) from healthy donors alleviates most disease manifestations in MPS I-H patients, likely by migration of the transplant-derived leukocytes into organs, where they can clear the storage and secrete the functional enzyme for correction of the metabolic defect in resident cells. 3 However, despite recent improvements in the outcome of HCT, the morbidity and mortality associated with the procedure are still not negligible, mostly due to rejection and graft-versus-host disease. Moreover, the amount of enzyme that transplantation can provide to the organism can be limiting, especially since donors are often heterozygous siblings. Indeed, a relationship between circulating enzyme levels after transplant and urinary GAGs has been shown 4 : the low enzyme levels achieved with heterozygote donor transplant lead to less adequate reduction in GAG levels. Likely due to partial metabolic correction at disease sites, the impact of HCT on central nervous system (CNS) and skeletal disease, despite being substantial in ameliorating patients' phenotype, could still benefit from further improvement. 5 The benefits of different gene therapy approaches were established in MPS I animal models. Intravenous delivery of viral vectors, which can establish a tissue source for systemic enzyme distribution, was effective in controlling disease manifestations in The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by guest www.bloodjournal.org From MPS I animal models upon neonatal treatment. [6][7][8][9] However, residu...

Adenosine deaminase (ADA) deficiency is a disorder of the purine metabolism leading to combined immunodeficiency and systemic alterations, including skeletal abnormalities. We report that ADA deficiency in mice causes a specific bone phenotype characterized by alterations of structural properties and impaired mechanical competence. These alterations are the combined result of an imbalanced receptor activator of nuclear factor-B ligand (

The liver is the current site for pancreatic islet transplantation, but has many drawbacks due to immunologic and nonimmunologic factors. We asked whether pancreatic islets could be engrafted in the bone marrow (BM), an easily accessible and widely distributed transplant site that may lack the limitations seen in the liver. Syngeneic islets engrafted efficiently in the BM of C57BL/6 mice rendered diabetic by streptozocin treatment. For more than 1 year after transplantation, these animals showed parameters of glucose metabolism that were similar to those of nondiabetic mice. Islets in BM had a higher probability to reach euglycemia than islets in liver (2.4-fold increase, P ‫؍‬ .02), showed a compact morphology with a conserved ratio between ␣ and ␤ cells, and affected bone structure only very marginally. Islets in BM did not compromise hematopoietic activity, even when it was strongly induced in response to a BM aplasia-inducing infection with lymphocytic choriomeningitis virus.

The osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL)/receptor activator of nuclear factor-κB (RANK) system was evaluated as a potential target of CGRP anabolic activity on bone. Primary cultures of human osteoblast-like cells (hOB) express calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1, and, because CGRP stimulates cAMP (one of the modulators of OPG production in osteoblasts), it was investigated whether it affects OPG secretion and expression in hOB. CGRP treatment of hOB (10−11 M–10−7 M) dose-dependently inhibited OPG secretion with an EC50 of 1.08 × 10−10 M, and also decreased its expression. This action was blocked by the antagonist CGRP8–37. Forskolin, a stimulator of cAMP production, and dibutyryl cAMP also reduced the production of OPG. CGRP (10−8 M) enhanced protein kinase A (PKA) activity in hOB, and hOB exposure to the PKA inhibitor, H89 (2 × 10−6 M), abolished the inhibitory effect of CGRP on OPG secretion. Conditioned media from CGRP-treated hOB increased the number of multinucleated tartrate-resistant acid phosphatase-positive cells and the secretion of cathepsin K in human peripheral blood mononuclear cells compared with the conditioned media of untreated hOB. These results show that the cAMP/PKA pathway is involved in the CGRP inhibition of OPG mRNA and protein secretion in hOB and that this effect favors osteoclastogenesis. CGRP could thus modulate the balance between osteoblast and osteoclast activity, participating in the fine tuning of all of the bone remodeling phases necessary for the subsequent anabolic effect.

Transgenic mice over-expressing calcitonin gene-related peptide (CGRP) in osteoblasts have increased bone density due to increased bone formation, thus suggesting that CGRP plays a role in bone metabolism. In this study we determined the relationship between CGRP, the canonical Wnt signaling and apoptosis in human osteoblasts (hOBs) in consideration of the well-documented involvement of this pathway in bone cells. Primary cultures of hOBs were treated with CGRP 10(-8) M. Levels of β-catenin, which is the cytoplasmic protein mediator of canonical Wnt signaling, and mRNA were determined. CGRP increases both the expression and the levels of cytoplasmic β-catenin by binding to its receptor, as this effect is blocked by the antagonist CGRP(8-37). This facilitatory action on β-catenin appears to be mediated by the inhibition of the enzyme GSK-3β via protein kinase A (PKA) activation. GSK-3β is a glycogen synthase kinase that, by phosphorylating β-catenin, promotes its degradation by the proteosomal machinery. Moreover, the peptide is able to inhibit hOBs apoptosis stimulated by dexamethasone or by serum deprivation, possibly through the accumulation of β-catenin, since the inhibitor of PKA activity H89 partially prevents the antiapoptotic effect of the peptide. In conclusion CGRP, released by nerve fibers, exerts its anabolic action on bone cells by stimulating canonical Wnt signaling and by inhibiting hOBs apoptosis, thus favoring local bone regeneration.