Overexpression of spermidine/spermine N 1-acetyltransferase impairs osteoblastogenesis and alters mouse bone phenotype

Abstract

Spermidine/spermine N (1)-acetyltransferase (SSAT) is a catabolic regulator of polyamines, ubiquitous molecules essential for cell proliferation and differentiation. In pathological conditions, the increased polyamine catabolism has been shown to mediate its cellular functions not only by changed polyamine levels but also by the availability of metabolites shared with other metabolic pathways or by production of toxic compounds. Our previous results showed that mice overexpressing SSAT (SSAT mice) developed a myeloproliferative disease and the bone marrow microenvironment partly contributed to its development. In this study, the physiological role of SSAT and polyamines in bone remodeling was characterized. Skeletal development of the SSAT mice appeared outwardly similar to wild-type mice until maturity, after which the SSAT mice developed kyphosis. With aging, the SSAT overexpression elicited increased bone perimeter with strikingly thinned cortical bone, decreased trabecular thickness and increased trabecular number in mice. In vitro studies showed that the maturation of SSAT overexpressing osteoblasts was impaired and the expression of bone formation marker genes was dramatically decreased. The polyamine pattern in osteoblasts of SSAT mice was distorted in comparison with wild-type mice. However, treatment of osteoblasts with a SSAT-inducing functional polyamine analogue suggested that defective osteoblastogenesis resulted rather from other consequences of enhanced SSAT activity than lowered levels of the higher polyamines. In comparison to SSAT overexpressing mice, SSAT deficiency led to opposite changes in osteoblastogenesis and differences in bone phenotype in mice. In conclusion, the level of SSAT enzyme activity affected osteoblastogenesis and hence influenced bone remodeling and the bone phenotype in mice. Furthermore, our results suggest the contribution of the catabolic part of the polyamine cycle, other than polyamine depletion, in pathophysiological processes of bone remodeling.

Activation of Polyamine Catabolism by N1,N11-Diethylnorspermine in Hepatic HepaRG Cells Induces Dedifferentiation and Mesenchymal-Like Phenotype

“…Similar results were also reported in the case of ODC down-regulation by RNAi or inhibition using DFMO [57]. Overexpression of SSAT in mice altered the hematological phenotype by inducing proliferation of myeloid cells [58] as well as impaired osteoblastogenesis [59]. Among other cell types, whose differentiation is dependent on polyamines are myoblasts [60], germ cells [61], and keratinocytes [62].…”

FGFR3 is a positive regulator of osteoblast expansion and differentiation during zebrafish skull vault development

“…In fgfr3 lof1/lof1 osteoblasts, we observed the downregulation of sat1a.2, coding for the spermidine/spermine N1-acetyltransferase 1a, duplicate 2 -a catabolic regulator of polyamine ( Figure 8A). Polyamines and Ssat (the mouse ortholog of sat1a.2) are reportedly positive regulators of osteogenesis (Lee et al, 2013;Pirnes-Karhu et al, 2015). In fgfr3 lof1/lof1 late osteoprogenitors, we noted the downregulation of inhibitor of differentiation 2 (id2b) coding for one of the Id proteins that promote osteoprogenitor proliferation and inhibit terminal differentiation (Peng et al, 2004).…”

Gamma-Glutamylpolyamine Synthetase GlnA3 Is Involved in the First Step of Polyamine Degradation Pathway in Streptomyces coelicolor M145

“…In eukaryotes, polyamines have been described to be implicated in cell growth and development (Pirnes-Karhu et al, 2015; Reis et al, 2016), maturation (Zhou et al, 2009; Tsaniklidis et al, 2016) and proliferation (Heby, 1981; Dudkowska et al, 2003; Maeda et al, 2006; Bercovich et al, 2011; Weiger and Hermann, 2014). They were also reported to be involved in environmental stress response (Valdes-Santiago and Ruiz-Herrera, 2013; Alcazar and Tiburcio, 2014; Minocha et al, 2014; Liu et al, 2015; Pal et al, 2015), defense response (Walters, 2003; Wimalasekera et al, 2011; Zeier, 2013; Hatmi et al, 2014; Mo et al, 2015; Rossi et al, 2015) and apoptosis (Moschou and Roubelakis-Angelakis, 2014; Parhamifar et al, 2014; Cai et al, 2015).…”