New insights into NPP1 function: Lessons from clinical and animal studies

Abstract

The recent elucidation of rare human genetic disorders resulting from mutations in ectonucleotide pyrophosphotase/phosphodiesterase (ENPP1), also known as plasma cell membrane glycoprotein 1 (PC-1), has highlighted the vital importance of this molecule in human health and disease. Generalised arterial calcification in infants (GACI), a frequently lethal disease, has been reported in recessive inactivating mutations in ENPP1. Recent findings have also linked hypophosphataemia to a lack of NPP1 function. A number of human genetic studies have indicated that NPP1 is a vital regulator that influences a wide range of tissues through various signalling pathways and when disrupted can lead to significant pathology. The function of Enpp1 has been widely studied in rodent models, where both the mutant tiptoe walking (ttw/ttw) mouse and genetically engineered Enpp1(-/-) mice show significant alterations in skeletal and soft tissue mineralisation, calcium/phosphate balance and glucose homeostasis. These models therefore provide important tools with which to study the potential mechanisms underpinning the human diseases associated with altered NPP1. This review will focus on the recent advances in our current knowledge of the actions of NPP1 in relation to bone disease, cardiovascular pathologies and diabetes. A fuller understanding of the mechanisms through which NPP1 exerts its pathological effects may stimulate the development of novel therapeutic strategies for patients at risk from the devastating clinical outcomes associated with disrupted NPP1 function.

Mineralisation of collagen rich soft tissues and osteocyte lacunae in Enpp1 mice

“…In particular, the global ablation of Enpp1 −/− function has provided considerable information about the actions of NPP1 in different tissues (see review by Mackenzie et al 2012 [18]). Within bone, the effects of NPP1 on osteoblast differentiation and function have been well documented [20,27,28], yet information regarding its role in osteocytes and osteoclasts is limited.…”

Juxta-articular joint-capsule mineralization in CD73 deficient mice: Similarities to patients withNT5Emutations

“…12,23 For example, generation of the Abcc6 -/-mice as a model for PXE has greatly facilitated the understanding of the pathomechanistic features of this complex disorder. 24,25 Similarly, generation of targeted mutant Enpp1 ¡/¡ mice or identification of spontaneous Enpp1 mutant mice, such as asj and ttw, have provided novel insight into the mineralization processes in GACI.…”

Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

“…Thus, NPP1 has been identified as a critical regulator of tissue mineralisation, hydrolysing nucleotides into extracellular inorganic pyrophosphate (PPi), a potent inhibitor of HA crystal formation in mineralisation-competent tissues (Terkeltaub 2001). Mice lacking NPP1 (Enpp1 K/K ) have severe mineralisation defects in long bones and calvariae, with pathological perispinal soft tissue and medial arterial mineralisation associated with abnormally low PPi levels (Sali et al 1999, Anderson et al 2005, Mackenzie et al 2012a. In addition to its recognised roles in mineralisation, increased NPP1 expression has been associated with insulin resistance in both in vitro and in vivo models by negatively modulating IR signalling.…”