COMPARATIVE ENDOCRINOLOGY

By Q. CALIO

CONTENTS 1 THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY ABSTRACT INTRODUCTION: AN OVERVIEW OF FGF-FGFR SIGNALING HS MODULATES FGF SIGNALING THROUGH MULTIPLE MECHANISMS PARACRINE FGFS MEDIATE A MESENCHYMAL-EPITHELIAL SIGNALING LOOP WITHIN TISSUES ENDOCRINE FGFS REGULATE KEY METABOLIC PROCESSES IN A KLOTHO-DEPENDENT FASHION THE MOLECULAR BASIS FOR THE FGF19 SUBFAMILY’S KLOTHO CORECEPTOR REQUIREMENT TO FGFR CHARACTERIZATION OF THE BINDING OF FGF23 TOKLOTHO PHARMACOLOGICAL IMPACT OF STRUCTURAL INSIGHTS INTO FGF19 SUBFAMILY CONCLUSION 2 KLOTHO AND KLOTHO INTRODUCTION PHENOTYPES OF KLOTHO/ MICE KLOTHO PROTEIN FUNCTION PHOSPHATE HOMEOSTASIS A POTENTIAL LINK BETWEEN PHOSPHATE AND AGING SECRETED KLOTHO KLOTHO KLPH NUCLEAR RECEPTOR REGULATION OF ENDOCRINE FGFS 3 FGF23 AND SYNDROMES OF ABNORMAL RENAL PHOSPHATE HANDLING AUTOSOMAL DOMINANT HYPOPHOSPHATEMIC RICKETS (ADHR, OMIM 193100) OTHER DISORDERS OF RENAL PHOSPHATE EXCRETION INHERITED HYPOPHOSPHATEMIC DISORDERS OTHER THAN ADHR HYPERPHOSPHATEMIC DISORDERS 4 EVIDENCE FOR FGF23 INVOLVEMENT IN A BONE-KIDNEY AXIS REGULATING BONE MINERALIZATION AND SYSTEMIC PHOSPHATE AND VITAMIN D HOMEOSTASIS EVOLVING INSIGHTS INTO SKELETAL FUNCTIONS PHYSIOLOGICAL FUNCTIONS OF FGF23 5 FGF23, KLOTHO AND VITAMIN D INTERACTIONS: WHAT HAVE WE LEARNED FROM IN VIVO MOUSE GENETICS STUDIES? FGF23 FGF23 AND CKD FGF23 SIGNALING IN VIVO IMPORTANCE OF KLOTHO IN FGF23 FUNCTION VITAMIN D AND FGF23-KLOTHO AXIS 6 FGF23 AND THE PARATHYROID EFFECT OF FGF23 ON THE PARATHYROID EXPRESSION OF KLOTHO IN THE PARATHYROID FUNCTIONAL EFFECT OF FGF23 ON PTH EXPRESSION FGF23 ACTIVATES MAPK IN THE PARATHYROID FGF23 ACTS ON BOVINE PARATHYROID CELLS TO DECREASE PTH AND INCREASE 25(OH) VITAMIN D 1 HYDROXYLASE EXPRESSION FGF23 DECREASES SERUM PTH LEVELS IN TRANSGENIC MICE EXPRESSING THE HUMAN PTH GENE FGF23 IN CHRONIC KIDNEY DISEASE (CKD) THE MECHANISM OF THE RESISTANCE TO FGF23 IN THE PARATHYROID THE MECHANISM OF THE INCREASED FGF23 LEVELS IN CKD 7 REGULATION OF ION CHANNELS BY SECRETED KLOTHO HOMOLOGY WITH THE FAMILY 1 GLYCOSIDASES AND THE GLUCURONIDASE ACTIVITY OF KLOTHO SIALIDASE ACTIVITY AND REGULATION OF ION CHANNELS BY SECRETED KLOTHO CONTROL OF THE RESIDENT TIME OF MEMBRANE GLYCOPROTEINS VIA GALECTIN-N-GLYCAN INTERACTION REGULATION OF ION CHANNELS BY SECRETED KLOTHO VIA OTHER MECHANISMS ROLE OF REGULATION OF TRPV5 BY SECRETED KLOTHO IN THE OVERALL ANTI-AGING FUNCTION OF KLOTHO CONCLUSION AND FUTURE PERSPECTIVES 8 FGF23 IN CHRONIC KIDNEY DISEASE INTRODUCTION: BURDEN OF CHRONIC KIDNEY DISEASE OVERVIEW OF NORMAL MINERAL METABOLISM AND ITS DISORDERS IN CKD DISORDERED PHOSPHORUS METABOLISM AND ADVERSE CLINICAL OUTCOMES 9 SECRETED KLOTHO AND CHRONIC KIDNEY DISEASE KIDNEY: THE MAJOR SITE FOR KLOTHO SYNTHESIS MECHANISMS OF HOW SECRETED KLOTHO PRESERVES KIDNEY FUNCTION AND AMELIORATES COMPLICATIONS IN CKD VALUE OF MEASURING KLOTHO IN CKD POTENTIAL STRATEGIES TO INCREASE KLOTHO PROTEIN CONCLUSION AND PERSPECTIVES 10 FGF23 AS A NOVEL THERAPEUTIC TARGET BIOACTIVITIES OF RECOMBINANT PROTEIN OF FGF23 HYPOPHOSPHATEMIC RICKETS/OSTEOMALACIA DUE TO EXCESS ACTION OF FGF23 INHIBITION OF BIOACTIVITY OF CIRCULATING FGF23 IN HYPOPHOSPHATEMIC MICE THE POSSIBLE HORMONE REPLACEMENT THERAPY OF FGF23 IN TUMORAL CALCINOSIS 11 PHYSIOLOGY OF FGF15/19 DISCOVERY OF MOUSE FGF15 AND HUMAN FGF19 SIGNALING MECHANISMS FGF19 AND FGF15 ARE ORTHOLOGS REGULATION OF BILE ACID BIOSYNTHESIS REGULATION OF GALLBLADDER FILLING CHRONIC DIARRHEA AND DEFECTIVE ILEAL FGF19 RELEASE METABOLIC EFFECTS CONCLUSION AND FUTURE DIRECTIONS 12 FGF19 AND CANCER FGF19/FGF15 &' " #* KLOTHO CORECEPTOR FGF19 AND CANCER 13 UNDERSTANDING THE STRUCTURE-FUNCTION RELATIONSHIP BETWEEN FGF19 AND ITS MITOGENIC AND METABOLIC ACTIVITIES STRUCTURAL BASIS FOR THE INTERACTIONS BETWEEN FGF19 SUBFAMILY MEMBERS AND THEIR RECEPTORS ROLE OF FGFR4 IN GLUCOSE METABOLISM AND MITOGENESIS 14 FGF21 AS A THERAPEUTIC REAGENT FGF21 IN VITRO FINDINGS FGF21 GENETIC MODELS FGF21 CHRONIC AND ACUTE ADMINISTRATION IN VIVO FGF21 IN HUMANS