Abstract
X-linked hypophosphatemia (XLH) is characterized by rickets and osteomalacia, caused by inactivating mutations in the Phosphate-regulating endopeptidase homolog X-linked (PHEX) gene. With aging, adult patients develop paradoxical heterotopic calcifications of tendons and ligaments at their insertion sites (enthesophytes), and joint alterations. Understanding the progression of this structural damage that severely affects patients’ quality of life will help to improve the management of XLH. Here, we characterized the occurrence of enthesophytes and joint alterations through a 12 month in vivo micro-CT follow-up in the Hyp mouse, a murine model of XLH (n = 5 mice per group). Similar to adult patients with XLH, Hyp mice developed calcaneal enthesophytes, hip joint alterations, erosions of the sacroiliac joints and periarticular calcifications. These lesions were already present at month 3 and gradually worsened over time. In sharp contrast, no abnormalities were observed in control mice at early time points. Histological analyses confirmed the presence of bone erosions, calcifications and expansion of mineralizing enthesis fibrocartilage in Hyp mice and their absence in controls and suggested that new bone formation is driven by altered mechanical strain. Interestingly, despite a strong deformation of the curvature, none of the Hyp mice displayed enthesophyte at the spine. Peripheral enthesophytes and joint alterations develop at the early stages of the disease and gradually worsen overtime. Overall, our findings highlight the relevance of this preclinical model to test new therapies aiming to prevent bone and joint complications in XLH.
Highlights
Mineralization defects and paradoxical mineralization of entheses are the hallmarks of X-linked hypophosphatemia (XLH) (Polisson et al, 1985; Reid et al, 1989), a rare skeletal disease caused by inactivating mutations in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene (Sabbagh et al, 2000; Gaucher et al, 2009)
The burden of disease is related to musculoskeletal symptoms due to osteomalacia, osteoarthritis, and lower-limb muscle weakness, and ossification of entheses, this latter feature being a strong determinant of impairment in quality of life (QoL) in this population (Schott and Wills, 1976; Reid et al, 1989; Sullivan et al, 1992; Amora et al, 2006; Bergwitz and Juppner, 2009; Che et al, 2016; Skrinar et al, 2019)
We report that Hyp mice develop enthesopathies, joint ossifications and bone erosions relatively early in life, unlike WT mice
Summary
Mineralization defects and paradoxical mineralization of entheses are the hallmarks of X-linked hypophosphatemia (XLH) (Polisson et al, 1985; Reid et al, 1989), a rare skeletal disease caused by inactivating mutations in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene (Sabbagh et al, 2000; Gaucher et al, 2009). The current medical treatment, which is commonly prescribed from early childhood to the end of growth, seeks to address the deficiencies associated with this disease, i.e., oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogs (alfacalcidol or calcitriol) to counteract the 1,25-(OH)2-vitamin D deficiency (Glorieux et al, 1980; Friedman et al, 1993; Makitie et al, 2003; Liu et al, 2016) Despite this treatment during growth, musculoskeletal symptoms due to enthesopathies and osteoarthritis remain the main manifestations in the clinical progression of XLH (Carpenter, 2012; Linglart et al, 2014; Connor et al, 2015). The pathogenesis underlying the development and progression of enthesopathies and osteoarthritis in patients with XLH has yet to be investigated
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