FGF23 and Hypophosphatemic Rickets/Osteomalacia

Purpose of review X-linked hypophosphatemia and tumor-induced osteomalacia are diseases characterized by hypophosphatemia with impaired proximal tubular phosphate reabsorption. Complete resection of responsible tumors is the first line therapy for patients with tumor-induced osteomalacia. In contrast, phosphate and active vitamin D have been used for patients with X-linked hypophosphatemia and inoperable ones with tumor-induced osteomalacia. The purpose of this review is to summarize the pathogenesis of these diseases and discuss about the new treatment. Recent findings Excessive FGF23 production has been shown to underline several kinds of hypophosphatemic rickets/osteomalacia including X-linked hypophosphatemia and tumor-induced osteomalacia. Burosumab, an anti-FGF23 monoclonal antibody, was approved for clinical use while the indications of burosumab are different depending on countries. Summary The inhibition of excessive FGF23 activity has been approved as a new therapy for several kinds of hypophosphatemic diseases. Further studies are necessary to clarify the long-term effects and safety of burosumab

Skeletal FGFR1 signaling is necessary for regulation of serum phosphate level by FGF23 and normal life span

Fibroblast growth factor (FGF) 23 produced by the bone is the principal hormone to regulate serum phosphate level. Serum FGF23 needs to be tightly regulated to maintain serum phosphate in a narrow range. Thus, we hypothesized that the bone has some phosphate-sensing mechanism to regulate the production of FGF23. Previously we showed that extracellular phosphate induces the phosphorylation of FGF receptor 1 (FGFR1) and FGFR1 signaling regulates the expression of Galnt3, whose product works to increase FGF23 production in vitro. In this study, we show the significance of FGFR1 in the regulated FGF23 production and serum phosphate level in vivo. We generated late-osteoblast/osteocyte-specific Fgfr1-knockout mice (Fgfr1fl/fl; OcnCre/+) by crossing the Ocn-Cre and the floxed Fgfr1 mouse lines. We evaluated serum phosphate and FGF23 levels, the expression of Galnt3 in the bone, the body weight and life span. A selective ablation of Fgfr1 aborted the increase of serum active full-length FGF23 and the enhanced expression of Galnt3 in the bone by a high phosphate diet. These mice showed more pronounced hyperphosphatemia compared with control mice. In addition, these mice fed with a control diet showed body weight loss after 23 weeks of age and shorter life span. These results reveal a novel significance of FGFR1 signaling in the phosphate metabolism and normal life span

The Role of Bone-Derived Hormones in Glucose Metabolism, Diabetic Kidney Disease, and Cardiovascular Disorders

Bone contributes to supporting the body, protecting the central nervous system and other organs, hematopoiesis, the regulation of mineral metabolism (mainly calcium and phosphate), and assists in respiration. Bone has many functions in the body. Recently, it was revealed that bone also works as an endocrine organ and secretes several systemic humoral factors, including fibroblast growth factor 23 (FGF23), osteocalcin (OC), sclerostin, and lipocalin 2. Bone can communicate with other organs via these hormones. In particular, it has been reported that these bone-derived hormones are involved in glucose metabolism and diabetic complications. Some functions of these bone-derived hormones can become useful biomarkers that predict the incidence of diabetes and the progression of diabetic complications. Furthermore, other functions are considered to be targets for the prevention or treatment of diabetes and its complications. As is well known, diabetes is now a worldwide health problem, and many efforts have been made to treat diabetes. Thus, further investigations of the endocrine system through bone-derived hormones may provide us with new perspectives on the prediction, prevention, and treatment of diabetes. In this review, we summarize the role of bone-derived hormones in glucose metabolism, diabetic kidney disease, and cardiovascular disorders

Myxedema coma in COVID-19

SARS-CoV-2 infection is associated with thyroid disorders. It has been reported that myxedema coma (MC) can be complicated with COVID-19. COVID-19-related thyroid disorders consist of a broad spectrum of thyroid dysfunction, from thyrotoxicosis to decompensated hypothyroidism. It is possible that both primary and central thyroid disorders are induced by COVID-19 due to systemic inflammatory and immune responses. We experienced two cases in which patients with COVID-19 developed MC with central hypothyroidism. It is likely that MC affected the severity of COVID-19. It is necessary to consider the existence of MC during SARS-CoV-2 infection. We propose the potential mechanisms

Significance of Metformin Use in Diabetic Kidney Disease

Metformin is a glucose-lowering agent that is used as a first-line therapy for type 2 diabetes (T2D). Based on its various pharmacologic actions, the renoprotective effects of metformin have been extensively studied. A series of experimental studies demonstrated that metformin attenuates diabetic kidney disease (DKD) by suppressing renal inflammation, oxidative stress and fibrosis. In clinical studies, metformin use has been shown to be associated with reduced rates of mortality, cardiovascular disease and progression to end-stage renal disease (ESRD) in T2D patients with chronic kidney disease (CKD). However, metformin should be administered with caution to patients with CKD because it may increase the risk of lactic acidosis. In this review article, we summarize our current understanding of the safety and efficacy of metformin for DKD

Signaling pathways in diabetic nephropathy

Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), however, specific treatment for DN has not yet been elucidated. Therefore, it is critically important to understand the molecular mechanism underlying DN to develop cause-related therapeutic strategy. To date, various factors such as hemodynamic changes and metabolic pathways have been shown to be involved in the pathogenesis of DN. Excessive glucose influx activates cellular signaling pathways, including the diacylglycerol (DAG)-protein kinase C (PKC) pathway, advanced glycation endproducts (AGE), polyol pathway, hexosamine pathway and oxidative stress. These factors interact with one another, thereby facilitating inflammatory processes, leading to the development of glomerulosclerosis under diabetic conditions. In addition to metabolic pathways, Rho-kinase, an effector of small-GTPase binding protein Rho, has been implicated as an important factor in the pathogenesis of DN. A number of studies have demonstrated that Rho-kinase plays key roles in the development of DN by inducing endothelial dysfunction, mesangial excessive extracellular matrix (ECM) production, podocyte abnormality, and tubulointerstitial fibrosis. In this review article, we describe our current understanding of the signaling pathways in DN

Incretin-Based Therapies for Diabetic Complications: Basic Mechanisms and Clinical Evidence

An increase in the rates of morbidity and mortality associated with diabetic complications is a global concern. Glycemic control is important to prevent the development and progression of diabetic complications. Various classes of anti-diabetic agents are currently available, and their pleiotropic effects on diabetic complications have been investigated. Incretin-based therapies such as dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are now widely used in the treatment of patients with type 2 diabetes. A series of experimental studies showed that incretin-based therapies have beneficial effects on diabetic complications, independent of their glucose-lowering abilities, which are mediated by anti-inflammatory and anti-oxidative stress properties. Based on these findings, clinical studies to assess the effects of DPP-4 inhibitors and GLP-1RA on diabetic microvascular and macrovascular complications have been performed. Several but not all studies have provided evidence to support the beneficial effects of incretin-based therapies on diabetic complications in patients with type 2 diabetes. We herein discuss the experimental and clinical evidence of incretin-based therapy for diabetic complications

Renoprotective Effects of DPP-4 Inhibitors

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. Dipeptidyl peptidase (DPP)-4 inhibitors are widely used in the treatment of patients with type 2 diabetes (T2D). DPP-4 inhibitors reduce glucose levels by inhibiting degradation of incretins. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. It has been shown that an increased renal DPP-4 activity is associated with the development of DKD. A series of clinical and experimental studies showed that DPP-4 inhibitors have beneficial effects on DKD, independent of their glucose-lowering abilities, which are mediated by anti-fibrotic, anti-inflammatory, and anti-oxidative stress properties. In this review article, we highlight the current understanding of the clinical efficacy and the mechanisms underlying renoprotection by DPP-4 inhibitors under diabetic conditions