Low bone mineral density due to secondary hyperparathyroidism in the GlatmTg(CAG-A4GALT) mouse model of Fabry disease

Hiroki Maruyama; Atsumi Taguchi; Mariko Mikame; Hongmei Lu; Norihiro Tada; Muneaki Ishijima; Haruka Kaneko; Mariko Kawai; Sawako Goto; Akihiko Saito; Riuko Ohashi; Yuji Nishikawa; Satoshi Ishii

doi:10.1096/fba.2019-00080

Low bone mineral density due to secondary hyperparathyroidism in the Gla^tmTg(CAG-A4GALT) mouse model of Fabry disease

FASEB Bioadv. 2020 Jun 10;2(6):365-381. doi: 10.1096/fba.2019-00080. eCollection 2020 Jun.

Authors

Hiroki Maruyama¹, Atsumi Taguchi¹, Mariko Mikame¹, Hongmei Lu², Norihiro Tada², Muneaki Ishijima³, Haruka Kaneko³, Mariko Kawai⁴, Sawako Goto⁵, Akihiko Saito⁵, Riuko Ohashi⁶, Yuji Nishikawa⁷, Satoshi Ishii^{8

9}

Affiliations

¹ Department of Clinical Nephroscience Niigata University Graduate School of Medical and Dental Sciences Niigata Niigata Japan.
² Laboratory of Genome Research Research Institute for Diseases of Old Age Juntendo University Graduate School of Medicine Bunkyo-ku Tokyo Japan.
³ Department of Medicine for Orthopaedics and Motor Organ Juntendo University Graduate School of Medicine Bunkyo-ku Tokyo Japan.
⁴ Department of Pharmacology Osaka Dental University Hirakata Osaka Japan.
⁵ Department of Applied Molecular Medicine Niigata University Graduate School of Medical and Dental Sciences Niigata Niigata Japan.
⁶ Histopathology Core Facility Faculty of Medicine Niigata University Niigata Niigata Japan.
⁷ Division of Tumor Pathology Department of Pathology Asahikawa Medical University Asahikawa Hokkaido Japan.
⁸ Department of Matrix Medicine Faculty of Medicine Oita University Yufu Oita Japan.
⁹ Biochemical Laboratory GlycoPharma Corporation Oita Oita Japan.

Abstract

Low bone mineral density (BMD)-diagnosed as osteoporosis or osteopenia-has been reported as a new characteristic feature of Fabry disease; however, the mechanism underlying the development of low BMD is unknown. We previously revealed that a mouse model of Fabry disease [Gla^tmTg(CAG-A4GALT)] exhibits impaired functioning of medullary thick ascending limb (mTAL), leading to insufficient Ca²⁺ reabsorption and hypercalciuria. Here, we investigated bone metabolism in Gla^tmTg(CAG-A4GALT) mice without marked glomerular or proximal tubular damage. Low BMD was detected by 20 weeks of age via micro-X-ray-computed tomography. Bone histomorphometry revealed that low BMD results by accelerated bone resorption and osteomalacia. Plasma parathyroid hormone levels increased in response to low blood Ca²⁺-not plasma fibroblast growth factor 23 (FGF-23) elevation-by 5 weeks of age and showed progressively increased phosphaturic action. Secondary hyperparathyroidism developed by 20 weeks of age and caused hyperphosphatemia, which increased plasma FGF-23 levels with phosphaturic action. The expression of 1α-hydroxylase [synthesis of 1α,25(OH)₂D₃] in the kidney did not decrease, but that of 24-hydroxylase [degradation of 1α,25(OH)₂D₃] decreased. Vitamin D deficiency was ruled out as the cause of osteomalacia, as plasma 1α,25(OH)₂D₃ and 25(OH)D₃ levels were maintained. Results demonstrate that secondary hyperparathyroidism due to mTAL impairment causes accelerated bone resorption and osteomalacia due to hyperphosphaturia and hypercalciuria, leading to low BMD in Fabry model mice.

Keywords: 24‐hydroxylase; bone histomorphometry; osteomalacia; parathyroid hormone; renal phosphate wasting.