Hurler Disease Bone Marrow Stromal Cells Exhibit Altered Ability to Support Osteoclast Formation

Abstract

Mucopolysaccharidosis type I (MPS IH; Hurler syndrome) is a rare genetic disorder that is caused by mutations in the α-L-iduronidase (IDUA) gene, resulting in the deficiency of IDUA enzyme activity and intra-cellular accumulation of glycosaminoglycans. A characteristic skeletal phenotype is one of the many clinical manifestations in Hurler disease. Since the mechanism(s) underlying these skeletal defects are not completely understood, and bone and cartilage are mesenchymal lineages, we focused on the characterization of mesenchymal cells isolated from the bone marrow (BM) of 5 Hurler patients. IDUA-mutated BM stromal cells (BMSC) derived from MPS IH patients exhibited decreased IDUA activity, consistent with the disease genotype. The expansion rate, phenotype, telomerase activity, and differentiation capacity toward adipocytes, osteoblasts, chondrocytes, and smooth muscle cells in vitro of the MPS I BMSC lines were similar to those of BMSC from age-matched normal control donors. MPS I BMSC also had a similar in vivo osteogenic capacity as normal BMSC. However, MPS I BMSC displayed an increased capacity to support osteoclastogenesis, which may correlate with the up-regulation of the RANKL/RANK/OPG molecular pathway in MPS I BMSC compared with normal BMSC.

Comparative analysis of multilineage properties of mesenchymal stromal cells derived from fetal sources shows an advantage of mesenchymal stromal cells isolated from cord blood in chondrogenic differentiation potential

“…CB-MSCs and AF-MSCs at passage 3 were seeded at a density of 6 × 10 3 cells/cm 2 in basal medium, as previously described (25). After 48 h, medium was switched to osteogenic induction medium consisting of DMEM–low glucose (Invitrogen), supplemented with 10% FBS (Biosera), 100 nmol/L DEX (Invitrogen), 10 mmol/L B-glycerol-phosphate (Invitrogen) and 0.05 mmol/L 2-phosphate-ascorbic acid (Invitrogen).…”

Extracellular matrix disruption is an early event in the pathogenesis of skeletal disease in mucopolysaccharidosis I

“…Although the primary catabolic defect in MPS I is well characterized, the exact mechanisms of chondroosseous pathology remain unclear [1]. Research has begun to suggest that rather than being simple "storage diseases," complex pathogenic cascades drive and modify disease symptoms and complications in lysosomal diseases [1][2][3][4]. We hypothesize that activation of secondary pathogenic networks underlies chondro-osseous disease in MPS I, rather than pathogenesis being directly driven by storage of HS and DS.…”

Mesenchymal stem cells as cellular vectors for pediatric neurological disorders

“…These results suggest that the altered secretome displayed by GD-MSCs may contribute to skeletal and immune disease manifestations in these patients. Patients with Hurler’s syndrome also exhibit skeletal defects and examination of MSCs from these patients revealed an increased capacity to support osteoclastogenesis as compared to MSCs from unaffected controls (Gatto et al, 2012). The later was correlated with up regulation of the RANKL/RANK/OPG pathway in Hurler MSCs.…”