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Chronic Kidney Disease

Internal Medicine, Nephrology

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Nephrology and Kidney Diseases

Nephrology and Transplantation

Cellular fibroblast Progression Component: A Prospective Medical Goal

Correspondence to Author:  Xiao Li, 

Division of Nephrology, Department of Medicine, the University of Tennessee Health Science Center, Memphis,TN, 38165, USA.

Abstract: It has been discovered that fibroblast growth factor-23 (FGF-23) is a pathogenic factor and circulating hormone in a variety of medical diseases. Recent developments in FGF-23 as a therapeutic target are reviewed in this study, including FGF-23 antagonist, FGF-23 antibody, FGF-23 C-terminal peptide, CYP24A1 inhibitor, and fibroblast growth factor receptors (FGFR) tyrosine kinase inhibitor. We also provide an update on the benefits and drawbacks of focusing on downstream and upstream molecules in FGF-23 signalling pathways.

INTRODUCTION: A hormone generated from bone, fibroblast growth factor-23 (FGF 23) prevents the kidney from producing 1,25-dihydroxyvitamin D3 (1,25(OH)2D) and reabsorbing phosphate1,2 (Figure 1). Through the bone-kidney axis, FGF-23 physiologically controls vitamin D metabolism and systemic phosphate balance.3,4 Excess FGF-23, however, causes hyperphosphatemic rickets in hereditary diseases and may also be harmful in the course of chronic kidney disease.5-7 X-linked hypophosphatemic rickets (XLH)/Hyp mice, which is caused by inactivating mutations of Phex; autosomal recessive hypophosphatemic rickets 1 (ARHR1), which is caused by inactivating mutations of Dmp1,15,20 ARHR2, which is caused by inactivating mutations in ENPP1,10,14–17, and Raine Syndrome (RNS) are among the rare hereditary hypophosphatemic disorders in humans and their mouse homologues,8–19. caused by tumor-induced osteomalacia (TIO) and FAM20C21,22 inactivation mutations.23–25 Chronic kidney disease (CKD) is associated with secondary increases of FGF–23.1,26 Chronic elevations of FGF-23 are maladaptive and have been related to increased morbidity and mortality,6 cardiovascular disease,6,28–31, and inflammation32–33 in chronic kidney disease (CKD). Initially, elevated FGF-23 is an adaptive response to altered mineral metabolism in CKD27. Controlling FGF-23 levels and the signalling pathways that lead to and originate from it may therefore be a viable target to enhance outcomes in a variety of medical disorders. The tyrosine kinase inhibitor (NVP-BGJ398) for fibroblast growth factor receptors (FGFR),34,35 CYP24A1 inhibitor,36 FGF-23 antibody (KRN23),37,38 FGF-23C-terminal peptide,39,40 are being developed to treat illnesses caused by excess FGF-23, as is FGF-23 antagonist 41. Recent developments in these fields will be summed up in this review.

FGFR INHIBITOR KINASE:The pharmacological suppression of FGFRs in excess FGF-23 is strongly supported by data. First, the important co-receptor Klotho works with members of the FGF receptor (FGFRs, 1, 3, 4) family to transduce FGF-23 signalling. This process gives endocrine FGF-23 signals tissue-specificity because of its kidney’s major expression (Figure 1).42 Second, FGFR signalling and FGF-23 expression are activated in osteocytes17 in hereditary hypophosphatemic diseases such XLH/Hyp and ARHR1, and osteocyte-specific Fgfr1 deletion in Hyp animals significantly reduces FGF-23 production.18 Third, osteoglophonic dysplasia (OGD) is caused by a gain-of-function mutation in FGFR1, and it is also linked to hypophosphatemia and increased FGF-23 levels.43 The development of FGFR inhibitors that regulate FGF-23 signalling and production in disorders of excess could be beneficial in theory.To treat FGF-23-mediated hypophosphatemic disorders, FGFR tyrosine kinase inhibitor (NVP-BGJ398) has been created. It has been demonstrated to limit FGF-23’s production as well as its effects on end organs.34, 35 However, NVP-BGJ398 is a tiny drug that lacks selectivity for FGF-23/FGFR/α-KL signalling and has strong inhibitory action against FGFRs 1, 3, and 4. As a result, its broad potential to block FGFRs across several tissues would be unfavourable.34, 35 Furthermore, it has been revealed that SSR128129E (SSR), a tiny molecule that binds to the extracellular portion of FGFR, functions as a FGFR antagonist.44, 45 Since SSR128129E has certain drawbacks, including as selectivity and possible toxicity, it is currently being explored as an anti-tumor medication. There aren’t any little compounds available yet that precisely control FGF-23 activation. The identification of such molecules would progress the hunt for innovative treatments based on this unique bone/kidney endocrine network, in addition to offering research instruments to clarify FGF-23 biological functions.

FGF-23 Antibody: A FGF-23 specific antibody has been developed as a treatment for XLH (Burosumab, KRN23, Ultragenix (USA) and Kirin (Japan)).37, 38, and 46 KRN23 attaches to FGF-23 and prevents its biological function. But the loss of FGF-23 function can lead to major adverse effects, such as calcifications of soft tissues and hyperphosphatemia. There are currently no plans to investigate KRN23 in CKD because preclinical research in CKD models indicates that inhibiting FGF-23 with a high affinity blocking antibody increases mortality (38). It is debatable whether to lower FGF-23 in CKD because using calcimimetics to reduce PTH only slightly lowersand increased longevity in those suffering from end-stage kidney disease (ESRD).47 Finding a medication to dose-dependently and reversibly lower FGF-23 may improve the course of CKD, as an estimated 30 million adults in the USA, or 15% of the population, have CKD with increased FGF 23. A low affinity FGF-23 blocking antibody (KRN23) was chosen for clinical development in order to minimise harm. KRN23 is effective in improving rickets in XLH patients by elevating serum phosphate, according to clinical trials.37, 38 While ~6% of XLH patients treated with KRN23 experienced hyperphosphatemia, biologics like KRN23 have several drawbacks, including high cost, parenteral delivery required, lengthy half-life, and challenges with dose titration. From a commercial standpoint, it is possible to create a tiny, orally accessible chemical that inhibits FGF-23.

C-TERMINAL PEPTIDES OF FGF-23: A biological endoproteasefur can cleave the 32-kDa full-length FGF-23 protein at the 176RXXR179 location, resulting in the portions of the 16-kDa C-terminal and 22-kDa N-terminal. Thirteen According to recent research, FGF-23C’s C-terminal tail can rival full-length ligand for binding to the FGFR/α-KL complex. As a result, it can counteract FGF-23’s phosphaturic activity in vivo in both mice with phosphate deficiency illnesses and healthy rats.39, 40 The researchers created a FGF-23C Fc fusion molecule to extend the half-life of the FGF-23C peptide. They then showed that injecting this molecule twice a week at a dose of 10 mg/kg selectively regulates the phosphate pathway by controlling NPT2A expression in vivo through competitive inhibition of FGF-23 binding. To the Hypmice preclinical model of XLH/FGFR/α-KL co-receptor.With limited safety concerns, the FGF-23C Fc molecule is an ideal candidate for use as a new therapeutic for XLH patients. Its ability to preferentially modulate the FGFR1/α-KL phosphate pathway, but not FGFR3&4/α-KL, in the control of 1,25(OH)2D levels in the kidney, makes it a unique tool for treating the disease.39, 40

CYP24A1 INHIBITOR: In order to reduce the amount of renal 1,25(OH)2D produced, FGF-23 either upregulates the expression of vitamin D 24-hydroxylase (CYP24A1), a mitochondrial enzyme that inactivates vitamin D metabolites through the C-24 oxidation pathway, or inhibits the expression of CYP27B1, the enzyme that converts 25-(OH)D to its active metabolite.49 In the mice models of hyperexpressing mutant FGF23R176Q and Hyp, hypophosphatemic rickets with elevated levels of FGF-23 are similarly linked to higher renal CYP24A1 expression, indicating a critical role for enhanced CYP24A1 activity in the pathogenesis of these diseases.In the Hyp and FGF23R176Q-transgenic mice, CYP24A1 knockout led to almost full recovery of rachitic bone defects; nevertheless, blood phosphorus and 1,25(OH)2D levels did not increase in these murine models of human disease.36 It’s interesting to note that giving the CYP24A1 inhibitor CTA102 to Hyp and FGF23R176Q-transgenic mice improved their rachitic bones.36 It is yet unknown if pharmacologic inhibition of CYP24A1 activity can be used as a stand-alone therapeutic target.

FGF-23 INTERMEDIATOR: Apart from the FGF-23 C peptide and FGF-23 specific antibody, a FGF-23 antagonist (ZINC13407541) was identified computationally that binds to FGF-23 and interferes with its interaction with the FGFR/α-KL complex in a heterologous41 Additionally, it was demonstrated that this FGF-23 antagonist increased serum phosphate and 1,25(OH)2D in a mouse model of FGF-23-related hypophosphatemic illnesses and inhibited FGF-23 signalling in isolated renal tubules ex vivo.41 Furthermore, this FGF-23 antagonist raised PTH levels in the mouse illness model while marginally but considerably lowering FGF-23 levels.41 The discovery of a tiny chemical that inhibits FGF-23’s activation of FGFRs opens up new avenues for researching FGF-23’s functions and paves the way for the creation of therapeutic medication candidates to address conditions caused by excess FGF-23. In addition, compared to FGF-23 antibody, FGF-23 antagonist can be more affordable, orally accessible, and readily dose-titrated. This little chemical has been used in THREFGF-23TARGET EDTHERAPIES POTENTIAL SIDE EFFECTS Every FGF-23 focused treatment available today has benefits and drawbacks. The FGFR inhibitors exhibit a significant suppression of FGFR tyrosine kinase activity; they are able to obstruct FGF-23 production as well as its end-organ effects, but they are non-specific and may be harmful to tissues and organs. On the other hand, FGF-23 antibody exhibits a high level of treatment specificity while functioning as a FGF-23 blocker. FGF-23 antibody, however, requires expensive therapy and parenteral administration. Although FGF-23 C-terminal peptides similarly exhibit good treatment specificity, its potential as a long-term therapeutic strategy may be limited due to increased proteolytic instability during treatment.While the 52 CYP24A1 inhibitor has no effect on 1,25(OH)2D or phosphorus levels, it virtually entirely restores the rachitic bone in hypophosphatemic disorders. An FGF-23 antagonist may be a useful treatment approach as opposed to the FGF-23 antibody since it is efficient, orally accessible, and simple to dose titrate. This tiny molecule has been used in late clinical trials and preclinical screening to develop lead compounds.

The potential side effects of the target dietary supplements sEFGF-23: All of the available FGF-23 targeted treatments have benefits and drawbacks, as Table 1 illustrates. The FGFR inhibitors exhibit a significant suppression of FGFR tyrosine kinase activity; they are able to obstruct FGF-23 production as well as its end-organ effects, but they are non-specific and may be harmful to tissues and organs. On the other hand, FGF-23 antibody exhibits a high level of treatment specificity while functioning as a FGF-23 blocker. FGF-23 antibody, however, requires expensive therapy and parenteral administration. C-terminal peptides of FGF-23 also exhibit a high specificity ofWhile the 52 CYP24A1 inhibitor has no effect on 1,25(OH)2D or phosphorus levels, it virtually entirely restores the rachitic bone in hypophosphatemic disorders. If the short half-life of the chemical is addressed through optimisation, the FGF-23 antagonist’s oral bioavailability, dose titratability, and cost effectiveness make it a potentially useful treatment approach.

CONCLUSION: One hormone that circulates and controls the metabolism of phosphate and vitamin D is called fibroblast growth factor-23. Hypophosphatemic crickets and decreases in serum phosphate and 1,25(OH)2D levels are caused by over-action of FGF-23. Consequently, the development of treatment approaches to inhibit thathorm one’s behaviours is required. In fact, it has been observed that FGF-23 blocking antibodies or FGF-23 signalling inhibitors are beneficial for patients with hypophosphatemic diseases caused by excess FGF-23. 37, 53, and 54 However, because FGF-23 deficiency causes hyperphosphatemic illness, these medicines require close monitoring of dosage and use.55, 56 In fact, the management of FGF-23 levels in CKD patients appears to be controversial because mild FGF-23 reductions with calcimimetics may enhance survival in ESRD patients47, while FGF-23 inhibition with a high affinity blocking antibody increased mortality in CKD patients38, raising doubts about the efficacy of these novel therapies in CKD. For both inherited and acquired hyperphosphatemic disorders, the application of FGF 23 inhibitors or low affinity FGF-23 antibodies to regulate FGF 23 excess activities remains a viable treatment option.

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Xiao Li. Cellular fibroblast Progression Component: A Prospective Medical Goal. The Journal of Nephrology 2024.

Journal Info

  • Journal Name: The Journal of Nephrology
  • Impact Factor: 1.809*
  • ISSN: 2996-1750
  • DOI: 10.52338/tjon
  • Short Name: TJON
  • Acceptance rate: 55%
  • Volume: 6 (2024)
  • Submission to acceptance: 25 days
  • Acceptance to publication: 10 days


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