Magel2 Modulates Bone Remodeling and Mass in Prader-Willi Syndrome by Affecting Oleoyl Serine Levels and Activity

Abstract

Among a multitude of hormonal and metabolic complications, individuals with Prader-Willi syndrome (PWS) exhibit significant bone abnormalities, including decreased BMD, osteoporosis, and subsequent increased fracture risk. Here we show in mice that loss of Magel2, a maternally imprinted gene in the PWS critical region, results in reduced bone mass, density, and strength, corresponding to that observed in humans with PWS, as well as in individuals suffering from Schaaf-Yang syndrome (SYS), a genetic disorder caused by a disruption of the MAGEL2 gene. The low bone mass phenotype in Magel2 -/mice was attributed to reduced bone formation rate, increased osteoclastogenesis and osteoclast activity, and enhanced trans-differentiation of osteoblasts to adipocytes. The absence of Magel2 in humans and mice resulted in reduction in the fatty acid amide bone homeostasis regulator, N-oleoyl serine (OS), whose levels were positively linked with BMD in humans and mice as well as osteoblast activity. Attenuating the skeletal abnormalities in Magel2 -/mice was achieved with chronic administration of a novel synthetic derivative of OS. Taken together, Magel2 plays a key role in modulating bone remodeling and mass in PWS by affecting OS levels and activity. The use of potent synthetic analogs of OS should be further tested clinically as bone therapeutics for treating bone loss.

Thermoneutrality improves skeletal impairment in adult Prader–Willi syndrome mice

“…Indeed, this is the only model in which a comprehensive analysis has been made of the skeletal phenotype. Interestingly, although these mice also show comparable reductions in trabecular number, trabecular fragmentation, femoral strength and UTS to that reported here in the PWS-IC del mice, marrow adiposity is more than doubled (Baraghithy et al, 2019) compared to the profound reduction reported here. This implies that loss of one of the other genes in the PWS locus either disrupts the relationship between adipocyte and osteoblast differentiation, or the proliferation of MSCs.…”

“…Although overall body length is normal in the absence of Magel2 (Bischof et al, 2007), femoral length, cortical diameter and cortical wall thickness are reduced in female Magel2 del mice by 9-13% (Baraghithy et al, 2019). Indeed, this is the only model in which a comprehensive analysis has been made of the skeletal phenotype.…”

“…Similar results were obtained in females, the impaired biomechanical strength in PWS-IC del mice at 20-22°C (P=0.007), being ameliorated at thermoneutrality (P=0.215), as a consequence of the contribution of tissue strength, the impaired geometric contribution being exacerbated (P=0.006) (data not shown). Preliminary evidence of growth retardation has been reported in most of the murine models for PWS, including mice with uniparental disomy (Cattanach et al, 1992) and deletions of Snrpn-Ube3a (Tsai et al, 1999a), Snurf/Snrpn exon 2 (Tsai et al, 1999b), Snord116 (Ding et al, 2008) and Magel2 (Bischof et al, 2007;Baraghithy, 2019), with Necdin del mice showing normal growth (Tsai et al, 1999a). However, initial attempts to quantify skeletal growth following IC deletion, in which expression of all the genes in the PWS locus is lost, have been hampered by high neonatal mortality (Yang et al, 1998).…”

“…For example, there is a bi-directional relationship between fat and bone (Leiben et al, 2009), with bone marrow adipocytes and the bone-forming osteoblasts arising from the same mesenchymal stem cells (MSCs) (Beresford et al, 1992, Di Iorgi et al, 2008 and osteogenesis being influenced by leptin (Thomas et al, 1999, Hamrick et al, 2005, Evans et al, 2011. Although several studies have examined the effects of the loss of specific PWS interval regions/genes on bone (Khor et al, 2016, Kamaludin et al, 2016, Baraghithy et al, 2019, a study of the impact of losing all of the genes in the PWS locus is lacking. We have therefore conducted a study of the growth, morphology, microarchitecture and biomechanical properties of the appendicular bones of PWS-IC del mice and characterised the underlying endocrine phenotype.…”

Why and How Imprinted Genes Drive Fetal Programming

“…Studies of imprinted gene alteration, and SNP variation effects, indicate that biases toward paternal imprinted gene expression favor increased skeletal muscle mass, bone mass, and pancreatic β-cell mass, and reduced white fat mass [e.g., (31,(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)]. This paternal-gene tissue allocation pattern involves high demands on the mother for the protein, fat, minerals, and carbohydrates that lead to extensive insulin-fueled growth in lean mass, which is expected to benefit offspring inclusive fitness through large overall size, better physiological function, better early survival, and higher reproduction [e.g., (1,11)].…”