Genetic activation of Lrp5 increases bone mass in a Mouse Model for Enpp1-associated Early-Onset Osteoporosis

Introduction: The ectonucleotide pyrophosphatase/phosphodiesterase family member 1 (ENPP1) is the only known enzyme that facilitates the generation of the mineralization inhibitor pyrophosphate. Homozygous pathogenic variants of ENPP1 can cause general arterial calcification of infants and many survivors paradoxically develop hypophosphatemic rickets later in life. Furthermore, heterozygous carriers of pathogenic variants can develop early-onset osteoporosis with the associated increased fracture risk and decreased quality of life. While the underlying mechanism is currently not fully understood, treatment of these patients is currently achieved by anti-resorptive medication. With the advent of the highly potent osteoanabolic antibody against Sclerostin (i.e. romosozumab), a novel and promising treatment option to improve bone mass has become available. However, it has not been investigated, if such a treatment can also be effective in the context of ENPP1-associated osteoporosis and, even more importantly, if it may induce or exacerbate ectopic mineralization, as is observed in homozygous carriers of pathogenic ENPP1-variants.

Methods: To address this question, we first have determined that young (6-8 weeks) homozygous Enpp1asj2/asj2 mice are a suitable model system. They display significantly decreased trabecular bone mass while ectopic calcifications are not yet fully manifested and limited to mineralized tendons and spinal hyperostosis. In order to evaluate the effects of decreased Sclerostin activity, we crossed Enpp1asj2 mice with the Lrp5A213V mouse line. Here, Sclerostin can no longer bind to its target Lrp5, thereby genetically mimicking the pharmacological mechanism of antibody-mediated Sclerostin inhibition.

Results: Histomorphometric analysis of vertebral bodies from the resulting Enpp1asj2/asj2-Lrp5+/A213V mice revealed a significantly increased trabecular bone mass independent of the Enpp1 genotype compared to Lrp5-wildtype animals. Furthermore, radiographic analysis of the musculoskeletal system and histologic analysis of selected organs (heart, aorta, kidney and liver) indicated that the Lrp5+/A213V genotype has no significant impact on the occurrence and severity of ectopic calcifications.

Discussion: In conclusion, our data suggests that reducing Sclerostin activity may be an effective and safe option for the treatment of Enpp1-associated early-onset osteoporosis.

Keywords: Enpp1, ARHR, Early-Onset Osteoporosis, Treatment, Mouse Model

Korrespondenzadresse: Timur Alexander Yorgan, Universitätsklinikum Hamburg-Eppendorf, Institut für Osteologie und Biomechanik, Martinistr. 52, 20246 Hamburg, Deutschland, E-Mail: [e-mail]

 

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Publication History

Article published online:
21 March 2025