Bone Abstracts

Objective: Cystinosis is a rare lysosomal storage disorder caused by loss-of-function mutations of the CTNS gene, encoding for cystinosin symporter that mediates cysteine efflux from lysosome. ~95% of cystinotic patients display nephropathic Fanconi’s syndrome, short stature, osteopenia and rickets. In this study we evaluated whether the absence of cystinosin primarily affects bone remodeling activity.

Methods: We analyzed bone phenotype of ctns−/− (KO) male mice lacking of nephropathy. Intra-lysosomal cystine accumulation in tissues was detected by HPLC. Bone phenotype was evaluated by μCT, transcriptomic and bone serum biomarkers analysis. In vitro study was performed to evaluate the differentiation and activity of osteoblasts.

Results: Intra-lysosomal cystine accumulates in Ctns−/− bones during life reaching higher levels than those observed in kidney. Cystinosin is expressed in human and murine osteoblasts and osteoclasts; interestingly its expression increases during osteoclastogenesis. μCT analysis showed a reduction of trabecular bone volume (BV/TV % WT: 16.43±0.62; KO: 12.22±0.59; P<0.05) and bone mineral density in 1-month-old KO mice (BMD mgHA/cm³ WT: 194.01±4.04; KO: 158.02±6.00; P<0.05) with a decrease of trabecular number and thickness. P1NP serum levels were reduced in KO samples compared to WT (P1NP ng/ml WT: 1130±42.48; KO: 931.6±40.52; P<0.05). Furthermore a reduction of alp and col1a2 expression in femurs of KO mice was observed. In vitro analysis showed a reduced ALP positivity of KO osteoblasts with a decrease of alp, osterix and col1a2 gene expression compared to WT cultures.

Conclusions: Our study shows that cystinosin deficiency could primarily affects bone cells, leading to bone loss phenotype of KO mice, independently from renal tubulopathy.

Disclosure: The authors declared no competing interests.