Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease

Miguel Agustin Contreras (1) , William Louis Ries (1) , Srinivasan Shanmugarajan (1) , Gonzalo Arboleda (1) , Inderjit Singh (1) , Avtar Kaur Singh (2)

1 Department of Pediatrics
2 Department of Pathology and Laboratory Medicine

Krabbe disease is an inherited lysosomal disorder in which galactosylsphingosine (psychosine) accumulates mainly in the central nervous system. To gain insight into the possible mechanism(s) that may be participating in the inhibition of the postnatal somatic growth described in the animal model of this disease (twitcher mouse, ), we studied their femora. This study reports that femora are smaller than of those of wild type (), and present with abnormality of marrow cellularity, bone deposition (osteoblastic function), and osteoclastic activity. Furthermore, lipidomic analysis indicates altered sphingolipid homeostasis, but without significant changes in the levels of sphingolipid-derived intermediates of cell death (ceramide) or the levels of the osteoclast-osteoblast coupling factor (sphingosine-1-phosphate). However, there was significant accumulation of psychosine in the femora of adult animals as compared to , without induction of tumor necrosis factor-alpha or interleukin-6. Analysis of insulin-like growth factor-1 (IGF-1) plasma levels, a liver secreted hormone known to play a role in bone growth, indicated a drastic reduction in animals when compared to . To identify the cause of the decrease, we examined the IGF-1 mRNA expression and protein levels in the liver. The results indicated a significant reduction of IGF-1 mRNA as well as protein levels in the liver from as compared to littermates. Our data suggest that a combination of endogenous (psychosine) and endocrine (IGF-1) factors play a role in the inhibition of postnatal bone growth in mice; and further suggest that derangements of liver function may be contributing, at least in part, to this alteration.

Mots clés: IGF-1; SM; Sph; Sph-1P; Twi; CM; GH; GAPDH; qPCR; TRAP; Wt; Galactosylsphingosine; Insulin-like growth factor-1; Krabbe disease; lysosomal disorders; osteopenia; psychosine; twitcher mice

Miguel Agustin Contreras, William Louis Ries, Srinivasan Shanmugarajan, Gonzalo Arboleda, Inderjit Singh, et al.. Factors that affect postnatal bone growth retardation in the twitcher murine model of Krabbe disease. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2010, 1802 (7-8), pp.601. ⟨10.1016/j.bbadis.2010.04.006⟩. ⟨hal-00600125⟩