ABSTRACT
The type I transmembrane protein αKlotho (Klotho) serves as a coreceptor for the phosphaturic hormone fibroblast growth factor 23 (FGF23) in kidney, while a truncated form of Klotho (soluble Klotho, sKL) is thought to exhibit multiple activities, including acting as a hormone, but whose mode(s) of action in different organ systems remains to be fully elucidated. FGF23 is expressed primarily in osteoblasts/osteocytes and aberrantly high levels in the circulation acting via signaling through an FGF receptor (FGFR)-Klotho coreceptor complex cause renal phosphate wasting and osteomalacia. We assessed the effects of exogenously added sKL on osteoblasts and bone using Klotho-deficient (kl/kl) mice and cell and organ cultures. sKL induced FGF23 signaling in bone and exacerbated the hypomineralization without exacerbating the hyperphosphatemia, hypercalcemia and hypervitaminosis D in kl/kl mice. The same effects were seen in rodent bone models in vitro, in which we also detected formation of a sKL complex with FGF23-FGFR and decreased Phex (gene responsible for X-linked hypophosphatemic rickets (XLH)/osteomalacia) expression. Further, sKL-FGF23-dependent hypomineralization in vitro was rescued by soluble PHEX. These data suggest that exogenously added sKL directly participates in FGF23 signaling in bone and that PHEX is a downstream effector of the sKL-FGF23-FGFR axis in bone.
Subject(s)
Calcification, Physiologic/drug effects , Glucuronidase/genetics , Glucuronidase/pharmacology , Osteomalacia/genetics , Rickets/genetics , Animals , Animals, Newborn , Bone and Bones/drug effects , Bone and Bones/physiology , Cells, Cultured , Female , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/metabolism , Klotho Proteins , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Osteoblasts/drug effects , Osteoblasts/physiology , Osteocytes/drug effects , Osteocytes/physiology , Osteomalacia/blood , Osteomalacia/chemically induced , Osteomalacia/pathology , PHEX Phosphate Regulating Neutral Endopeptidase/drug effects , PHEX Phosphate Regulating Neutral Endopeptidase/metabolism , Pregnancy , Protein Isoforms/pharmacology , Rats , Rats, Wistar , Rickets/blood , Rickets/chemically induced , Rickets/pathology , Signal Transduction/drug effects , Signal Transduction/genetics , SolubilityABSTRACT
The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 PEX genes; defects in 14 of these have been shown to cause PBD. Three broad phenotypic groups are described on a spectrum of severity: Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate and infantile Refsum disease is less severe. Another group is Rhizomelic chondrodysplasia punctata spectrum. Recently, atypical phenotypes have been described, indicating that the full spectrum of these disorders remains to be identified. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome functions and PEX gene sequencing. There are no targeted therapies, although management protocols have been suggested and research endeavors continue. In this review we will discuss peroxisome biology and PBD, and research contributions to pathophysiology and treatment.
