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

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 [GlatmTg(CAG-A4GALT)] exhibits impaired functioning of medullary thick ascending limb (mTAL), leading to insufficient Ca2+ reabsorption and hypercalciuria. Here, we investigated bone metabolism in GlatmTg(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 1?-hydroxylase [synthesis of 1?,25(OH)2D3] in the kidney did not decrease, but that of 24-hydroxylase [degradation of 1?,25(OH)2D3] decreased. Vitamin D deficiency was ruled out as the cause of osteomalacia, as plasma 1?,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.

SUBMITTER: Maruyama H

PROVIDER: S-EPMC7325589 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Maruyama Hiroki H Taguchi Atsumi A Mikame Mariko M Lu Hongmei H Tada Norihiro N Ishijima Muneaki M Kaneko Haruka H Kawai Mariko M Goto Sawako S Saito Akihiko A Ohashi Riuko R Nishikawa Yuji Y Ishii Satoshi S

FASEB bioAdvances 20200610 6

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 [GlatmTg(CAG-A4GALT)] exhibits impaired functioning of medullary thick ascending limb (mTAL), leading to insufficient Ca2+ reabsorption and hypercalciuria. Here, we investigated bone metabolism in ...[more]

PMID: 32617522

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Project description:A subset of PHPT patients exhibit a more severe disease phenotype characterized by bone loss, fractures, recurrent nephrolithiasis, and other dysfunctions, but the underlying reasons for this disparity in clinical presentation remain unknown.We sought to identify new mechanistic indices that could inform more personalized management of PHPT.Pre-, peri-, and postoperative data and demographic, clinical, and pathological information from patients undergoing parathyroidectomy for PHPT were collected. Univariate and partial Spearman correlation was used to estimate the association of parathyroid tumor calcium sensing capacity with select variables.An unselected series of 237 patients aged >18years and undergoing parathyroidectomy for PHPT were enrolled.Calcium sensing capacity, expressed as the concentration required for half-maximal biochemical response (EC50), was evaluated in parathyroid tumors from an unselected series of 74 patients and assessed for association with clinical parameters. The hypothesis was that greater disease severity would be associated with attenuated calcium sensitivity and biochemically autonomous parathyroid tumor behavior.Parathyroid tumors segregated into two distinct groups of calcium responsiveness (EC50<3.0 and ?3.0mM). The low EC50 group (n=27) demonstrated a mean calcium EC50 value of 2.49mM [95% confidence interval (CI): 2.43-2.54mM], consistent with reference normal activity. In contrast, the high EC50 group (n=47) displayed attenuated calcium sensitivity with a mean EC50 value of 3.48mM [95% CI: 3.41-3.55mM]. Retrospective analysis of the clinical registry data suggested that high calcium EC50 patients presented with a more significant preoperative bone mineral density (BMD) deficit with a t-score of -2.7, (95% CI: -3.4 to -1.9) versus 0.9, (95% CI: -2.1 to -0.4) in low EC50 patients (p<0.001). After adjusting for gender, age, BMI, 25 OH vitamin D level and preoperative iPTH, lowest t-score and calcium EC50 were inversely correlated, with a partial Spearman correlation coefficient of -0.35 (p=0.02).Impaired calcium sensing in parathyroid tumors is selectively observed in a subset of patients with more severe bone mineral density deficit. Assessment of parathyroid tumor biochemical behavior may be a useful predictor of disease severity as measured by bone mineral density in patients with PHPT.

Project description:BACKGROUND:The patients with secondary hyperparathyroidism (SHPT) usually had reduced bone mineral density, which might lead to a substantial increase in osteoporosis, fracture and mortality. Although surgical intervention is effective in reducing parathyroid hormone (PTH) levels in suitable candidates refractory to medical therapy, the effect of surgery on bone mass changes still requires further evaluation. Thus, the aim of this study was to evaluate the characteristics of BMD changes after total parathyroidectomy (PTX) without autotransplantation and its associated factors. METHODS:The records of 34 patients who underwent successful total PTX without autotransplantation with a preoperative and postoperative dual energy X-ray absorptiometry (DEXA) scan in our institution within 4 years of operative intervention were reviewed. Correlation and regression analysis were used to identify factors that independently predict BMD changes. RESULTS:At baseline, we found that the prevalence of osteoporosis seemed to be much higher in the load-bearing lumbar spine than in the hip, varying greatly even between different lumbar vertebrae. The bone loss in SHPT had its predilection site in the load-bearing cancellous bone. After curative total PTX without autotransplantation, BMD improved significantly in both lumbar spine and hip overall. The largest increase in BMD occurred at L4 vertebrae with the lowest pre-operative BMD. At the most affected site L4, BMD improved in up to 94.1% of patients: 86.2% had significant improvement, 5.9% moderate improvement, and 5.9% declining bone mineral density. Correlation and regression analysis suggested that percentage changes in BMD were predicted negatively by the preoperative BMD and positively by the preoperative parathyroid mass but not intact PTH levels. CONCLUSION:Total parathyroidectomy without autotransplantation could improve BMD of secondary hyperparathyroidism at L1-L4 and the hip. Furthermore, the large parathyroid glandular mass and the preoperative BMD predicted the BMD changes after surgery.

Dataset Information

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

Publications

Low bone mineral density due to secondary hyperparathyroidism in the <i>Gla<sup>tm</sup>Tg(CAG-A4GALT)</i> mouse model of Fabry disease.

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