12.01.2023: The renal phosphate wasting disease X-linked hypophosphatemia (XLH) is a rare metabolic disorder of the bones associated with severe renal phosphate loss. The first symptoms of the genetic defect appear in childhood and adolescence and can significantly impair the quality of life. A recent study conducted by Helmholtz Munich with participation from the University of Veterinary Medicine Vienna used mass spectrometry imaging (MSI) to decipher, for the first time, important mechanisms underlying the dysregulated bone metabolism in XLH. According to the researchers, this opens up new potential approaches for the treatment of the disease.

A research team from Helmholtz Munich and Vetmeduni has for the first time characterised metabolic changes in XLH using mass spectrometry imaging. The researchers examined the bone tissue of a mouse strain that, similar to patients with XLH, had a PHEX gene variant causing an XLH-like phenotype. “We identified an upregulation of several biochemical pathways involving the mineralisation inhibitor pyrophosphate in the bone matrix of the mice. The imaging technique we used revealed complex changes in the metabolism of pentose phosphate, purines, pyrimidines and phospholipids in the bones of the animals,” explains study co-author Reinhold G. Erben, Head of the Department of Physiology, Pathophysiology and Experimental Endocrinology at Vetmeduni.

Basic research provides important new insights

According to the researchers, the study, which was recently published in JCI Insight, provides important new insights into the mechanisms underlying dysregulated bone metabolism in XLH and demonstrates for the first time the utility of MSI-based techniques for bone metabolomics. “Our study emphasises the great potential of spatial metabolomics in bone research, opening up new approaches to investigate a broad spectrum of bone diseases,” explains Axel Walch, Head of the Research Unit for Analytical Pathology at Helmholtz Munich. The findings of this groundbreaking basic research also provide new potential starting points for the treatment of the disease.

Phosphate imbalance leads to a variety of symptoms

Many biological processes rely on tightly regulated phosphate levels, and a deviation from the normal phosphate homeostasis leads to a variety of symptoms. The most prominent clinical problems in patients with XLH, such as leg deformities, dental diseases, skeletal pain and fractures, are caused by impaired bone mineralisation. Patients with XLH exhibit elevated levels of the bone-derived hormone FGF23 (fibroblast growth factor 23), which is known to regulate phosphate homeostasis. The hereditary disease is caused by inactivating mutations in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene. Until now, it had been unclear how the PHEX gene alters metabolism in bone.

The article “Spatial metabolomics reveals upregulation of several pyrophosphate-producing pathways in cortical bone of Hyp mice” by Achim Buck, Verena M. Prade, Thomas Kunzke, Reinhold G. Erben and Axel Walch was published in JCI Insight.

Scientific article