CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders

Xiu-juan, Bai; Miao, Dengshun; Xiao, S.; Dinghong, Qiu; St‐Arnaud, René; Petkovich, Martin; Gupta, Abhishek; Goltzman, David; Karaplis, Andrew C.

doi:10.1172/jci81928

Cited by 56 publications

(37 citation statements)

References 73 publications

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“…In this issue, Bai et al shed important new light on this controversy (4). Specifically, the authors investigated the role of CYP24A1, the cytochromal enzyme that catalyzes the first step in vitamin D degradation, in the pathogenesis of two prototypical disorders of primary FGF23 excess: X-linked hypophosphatemic rickets (XLH), which is caused by mutations in PHEX that lead to elevated FGF23 through unknown mechanisms, and autosomal dominant hypophosphatemic rickets (ADHR), which results from activating mutations in FGF23 itself.…”

Section: Targeting Cyp24a1 Ameliorates Skeletal Abnormalitiesmentioning

confidence: 98%

“…Bai and colleagues crossed Hyp mice, which are the murine homolog of human XLH and FGF23 transgenic mice, which overexpress the cleavage-resistant form of FGF23 (FGF23 R176Q ) produced in human ADHR, with Cyp24a1-null mice. As a secondary approach to evaluate the involvement of CYP24A1 in these diseases, Hyp and ADHR mice were also treated with a pharmacological CYP24A1 inhibitor (4).…”

Section: Targeting Cyp24a1 Ameliorates Skeletal Abnormalitiesmentioning

confidence: 99%

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Pruning the ricket thicket

David¹,

Wolf²

2016

Journal of Clinical Investigation

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Section: Targeting Cyp24a1 Ameliorates Skeletal Abnormalitiesmentioning

confidence: 98%

Section: Targeting Cyp24a1 Ameliorates Skeletal Abnormalitiesmentioning

confidence: 99%

Pruning the ricket thicket

David¹,

Wolf²

2016

Journal of Clinical Investigation

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“…(8) Bai and colleagues (51) show that inhibition of 24-hydroxylation with the 24-hydrxylase inhibitor CTA102 was able to heal the rachitic phenotype in both the hyp mouse and mice overexpressing FGF23. Although FGF23 regulation of 24-hydroxylation appears to play an important role in mice, this may not be true in humans.…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

“…The latest approach to be considered for treating FGF23 excess is the very recently reported inhibition of renal 24-hydroxylation of 25-hydroxyvitamin D with the 24-hydroxylase inhibitor, CTA102. (51) It is clear that in mice FGF23 simultaneously stimulates 24-hydroxylation while it inhibits 25-hydroxylation of vitamin D, shunting vitamin D production along the so-called degradation pathway. (8) Bai and colleagues (51) show that inhibition of 24-hydroxylation with the 24-hydrxylase inhibitor CTA102 was able to heal the rachitic phenotype in both the hyp mouse and mice overexpressing FGF23.…”

mentioning

confidence: 99%

“…(51) It is clear that in mice FGF23 simultaneously stimulates 24-hydroxylation while it inhibits 25-hydroxylation of vitamin D, shunting vitamin D production along the so-called degradation pathway. (8) Bai and colleagues (51) show that inhibition of 24-hydroxylation with the 24-hydrxylase inhibitor CTA102 was able to heal the rachitic phenotype in both the hyp mouse and mice overexpressing FGF23. Although FGF23 regulation of 24-hydroxylation appears to play an important role in mice, this may not be true in humans.…”

mentioning

confidence: 99%

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1,25-Dihydroxyvitamin D as Monotherapy for XLH: Back to the Future?

Ovejero

Gafni

Collins

2016

Journal of Bone and Mineral Research

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T he identification in the year 2000 of mutations in fibroblast growth factor 23 (FGF23) as the genetic cause of autosomal dominant hypophosphatemic rickets (ADHR) was a seminal discovery in the field of bone and mineral homeostasis.(1)Alterations in FGF23 levels were subsequently identified as the common abnormality in a number of phosphate homeostasis disorders, including X-linked hypophosphatemic rickets (XLH), (2) tumor-induced osteomalacia (TIO), (3) fibrous dysplasia of bone, (4) autosomal recessive hypophosphatemic rickets (ARHR), (5) cutaneous skeletal hypophosphatemia syndrome (CSHS), (6) familial tumoral calcinosis, (7) and others. The primary actions of FGF23 are to regulate blood phosphate and 1,25-dihydroxyvitamin D 3 (1,25-D) levels by its actions on renal sodium/phosphate cotransporters and 25-hydroxyvitamin D hydroxylation. (8) The fact that PTH, like FGF23, is also important in regulating phosphate and vitamin D homeostasis invokes the existence of an FGF23-Vitamin D-PTH axis that is key to many important aspects of bone and mineral biology. It is a complicated axis that involves the interaction of multiple receptors, a coreceptor, Klotho, (9) and multiple disparate but interacting signaling and enzymatic pathways. (10,11) Unraveling, in a hierarchical fashion, the roles of these complicated, intersecting, and overlapping pathways is important for both understanding mineral homeostasis physiology, and for the treatment of phosphate disorders. This has proved a significant challenge. Although a large number of very informative mouse models have been developed to understand and query this axis, at times the complexity of these models introduces potential confounders that are difficult to control for, and yield results inconsistent with observed human physiology. Thus, it is often difficult to understand and contextualize the findings and apply them to human mineral physiology and pathophysiology. The number of clinical studies conducted in this area is limited, and often focused on renal failure cohorts, the physiology of which differs significantly from those with normal renal function.Although a complete understanding of the FGF23-Vitamin D-PTH axis is lacking, there are a number of findings that are generally accepted to be true. These include: (1) FGF23 directly inhibits phosphate reabsorption and the generation of active vitamin D, 1,25-dihydroxyvitamin D 3 (1,25-D) at the level of the proximal renal tubule leading to a lowering of blood phosphate and 1,25-D levels (8) ; (2) in a classical feedback fashion, increases in blood phosphate and 1,25-D increase FGF23 levels (12,13) ; and (3) frank or relative FGF23-mediated reductions in serum 1,25-D lead to a compensatory increase in PTH, especially evident in the more severe forms of FGF23 excess such as TIO and renal failure. (14,15) The phosphaturic effects of increased PTH exacerbate the phosphate-lowering effects of FGF23 in patients with intact renal function such as TIO and XLH (reviewed in Blau and Collins (11) ). As for the hierarchic...

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Successful Management Of Tumor‐Induced Osteomalacia with Radiofrequency Ablation: A Case Series

et al. 2019

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Tumor‐induced osteomalacia (TIO) is a curable condition when the tumor is correctly located and completely removed. These tumors are, however, small and located in regions that make surgical removal difficult and sometimes risky in some patients. Experience of radiofrequency ablation (RFA) in the management of TIO is limited. We describe 3 patients with TIO who were treated in our hospital with RFA. They had suspected lesions in surgically difficult locations and were subjected to single sessions of RFA. The response was documented in terms of improvement in symptoms, normalization of hypophosphatemia and hyperphosphaturia, and disappearance of uptake on follow‐up Ga 68 DOTANOC PET/CT imaging. All 3 patients had a clinical and biochemical profile consistent with TIO. The first patient (patient 1) had an intensely Ga 68 DOTANOC avid lesion involving the roof of right acetabulum. The second patient (patient 2) had a Ga 68 DOTANOC avid intramuscular lesion in left pectineus muscle and the third patient (patient 3) had a Ga 68 DOTANOC avid expansile osteolytic lesion involving the angle and ramus of right mandible. All 3 patients achieved complete biochemical as well as clinical remission with single sessions of RFA. Six months after the procedure, Ga 68 DOTANOC imaging revealed the absence of uptake at the previous sites, corroborating with the clinical improvement and normalization of hypophosphatemia and hyperphosphaturia. In conclusion, although surgical resection is the standard of care, RFA can be used successfully for treating patients with TIO. It can be an effective, less invasive, and safe modality of treatment in those patients where resection of the lesion is not possible because of inaccessible anatomical location or comorbidity that prohibits surgery. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders

Cited by 56 publications

References 73 publications

Pruning the ricket thicket

Pruning the ricket thicket

1,25-Dihydroxyvitamin D as Monotherapy for XLH: Back to the Future?

Successful Management Of Tumor‐Induced Osteomalacia with Radiofrequency Ablation: A Case Series

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