Impact of Early Conventional Treatment on Adult Bone and Joints in a Murine Model of X-Linked Hypophosphatemia

Axelle Cauliez; Volha V Zhukouskaya; Stéphane Hilliquin; Jérémy Sadoine; Lotfi Slimani; Corinne Miceli-Richard; Karine Briot; Agnès Linglart; Catherine Chaussain; Claire Bardet

doi:10.3389/fcell.2020.591417

Impact of Early Conventional Treatment on Adult Bone and Joints in a Murine Model of X-Linked Hypophosphatemia

Front Cell Dev Biol. 2021 Feb 18:8:591417. doi: 10.3389/fcell.2020.591417. eCollection 2020.

Authors

Axelle Cauliez¹, Volha V Zhukouskaya^{1

2

3}, Stéphane Hilliquin^{1

4}, Jérémy Sadoine¹, Lotfi Slimani¹, Corinne Miceli-Richard⁴, Karine Briot^{3

4}, Agnès Linglart^{3

5}, Catherine Chaussain^{1

3

6}, Claire Bardet¹

Affiliations

¹ Université de Paris, Laboratory Orofacial Pathologies, Imaging and Biotherapies URP 2496 and FHU-DDS-Net, Dental School, and Plateforme d'Imagerie du Vivant (PIV), Montrouge, France.
² INTEGRARE, Genethon, Inserm, Université d'Evry, Université Paris-Saclay, Evry, France.
³ Centre de référence des maladies rares du métabolisme du calcium et du phosphate, Plateforme d'expertise maladies rares Paris Saclay, filière OSCAR, EndoRare and BOND ERN, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France.
⁴ Department of Rheumatology, Cochin Hospital, Université de Paris, Paris, France.
⁵ Université Paris-Saclay, AP-HP, Service d'endocrinologie et diabète de l'enfant, Service de médecine des adolescents, Hôpital de Bicêtre, INSERM U1185, Le Kremlin-Bicêtre, France.
⁶ AP-HP Reference Center for Rare Disorders of the Calcium and Phosphate Metabolism, Dental Medicine Department, Bretonneau Hospital, GHN, Paris, France.

Abstract

X-linked hypophosphatemia (XLH) is the most common form of genetic rickets. Mainly diagnosed during childhood because of growth retardation and deformities of the lower limbs, the disease affects adults with early enthesopathies and joint structural damage that significantly alter patient quality of life. The conventional treatment, based on phosphorus supplementation and active vitamin D analogs, is commonly administered from early childhood to the end of growth; unfortunately, it does not allow complete recovery from skeletal damage. Despite adequate treatment during childhood, bone and joint complications occur in adults and become a dominant feature in the natural history of the disease. Our previous data showed that the Hyp mouse is a relevant model of XLH for studying early enthesophytes and joint structural damage. Here, we studied the effect of conventional treatment on the development of bone and joint alterations in this mouse model during growth and young adulthood. Mice were supplemented with oral phosphorus and calcitriol injections, following two timelines: (i) from weaning to 3 months of age and (ii) from 2 to 3 months to evaluate the effects of treatment on the development of early enthesophytes and joint alterations, and on changes in bone and joint deformities already present, respectively. We showed that early conventional treatment improved bone microarchitecture, and partially prevented bone and joint complications, but with no noticeable improvement in enthesophytes. In contrast, later administration had limited efficacy in ameliorating bone and joint alterations. Despite the improvement in bone microarchitecture, the conventional treatment, early or late, had no effect on osteoid accumulation. Our data underline the usefulness of the Hyp murine model for preclinical studies on skeletal and extraskeletal lesions. Although the early conventional treatment is important for the improvement of bone microarchitecture, the persistence of osteomalacia implies seeking new therapeutic strategies, in particular anti-FGF23 approach, in order to optimize the treatment of XLH.

Keywords: Hyp mice; PHEX; XLH; conventional treatment; fibroblast growth factor 23; osteomalacia; phosphorus; rickets.