FGF23 Suppresses Chondrocyte Proliferation in the Presence of Soluble α-Klotho both in Vitro and in Vivo

Kawai, Masanobu; Kinoshita, Saori; Kimoto, Akihito; Hasegawa, Yasuhiro; Miyagawa, Kazuaki; Yamazaki, Miwa; Ohata, Yasuhisa; Ozono, Keiichi; Michigami, Toshimi

doi:10.1074/jbc.m112.410043

Cited by 49 publications

(45 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the current study, we identified Fgf23 as a strong transcriptional suppressor of TNAP in osteoblastic cells, acting through FGFR3 in a Klotho‐independent manner. In agreement with our findings, it was previously reported that Fgf23 binds to FGFR3 in vitro in chondrocytes . Hence, we hypothesize that Fgf23 secreted from osteocytes forms an autocrine/paracrine feedback loop in bone to indirectly regulate OPN secretion through TNAP.…”

Section: Discussionsupporting

confidence: 93%

FGF23 Regulates Bone Mineralization in a 1,25(OH)2D3 and Klotho-Independent Manner

Murali

Roschger

Zeitz

et al. 2015

Journal of Bone and Mineral Research

141

103

View full text Add to dashboard Cite

Fibroblast growth factor-23 (Fgf23) is a bone-derived hormone, suppressing phosphate reabsorption and vitamin D hormone (1,25(OH) 2 D 3 ) production in the kidney. It has long been an enigma why lack of Fgf23 or of Klotho, the coreceptor for Fgf23, leads to severe impairment in bone mineralization despite the presence of hypercalcemia and hyperphosphatemia. Using Fgf23 -/-or Klotho -/-mice together with compound mutant mice lacking both Fgf23 or Klotho and a functioning vitamin D receptor, we show that in Klotho -/-mice the mineralization defect is solely driven by 1,25(OH) 2 D 3 -induced upregulation of the mineralization-inhibiting molecules osteopontin and pyrophosphate in bone. In Fgf23 -/-mice, the mineralization defect has two components, a 1,25(OH) 2 D 3 -driven component similar to Klotho -/-mice and a component driven by lack of Fgf23, causing additional accumulation of osteopontin. We found that FGF23 regulates osteopontin secretion indirectly by suppressing alkaline phosphatase transcription and phosphate production in osteoblastic cells, acting through FGF receptor-3 in a Klotho-independent manner. Hence, FGF23 secreted from osteocytes may form an autocrine/paracrine feedback loop for the local fine-tuning of bone mineralization.

show abstract

Section: Discussionsupporting

confidence: 93%

FGF23 Regulates Bone Mineralization in a 1,25(OH)2D3 and Klotho-Independent Manner

Murali

Roschger

Zeitz

et al. 2015

Journal of Bone and Mineral Research

141

103

View full text Add to dashboard Cite

show abstract

“…Although we found in UMR-106 cells that an AG490-mediated increase in Fgf23 mRNA was potently induced, correlation between Fgf23 mRNA and FGF23 protein remains to be determined. Finally, there is emerging evidence that FGF23 is produced in cells that comprise bone outside of osteoblasts/osteocytes, such as chondrocytes (Kawai et al, 2013) and in marrow (Xiao et al, 2013). Therefore, whether these other sites compensate for osteoblast/osteocyte FGF23 production is currently unknown, and gives rise to the idea that in the Hyp genetic background, multiple cell types may have to be targeted to fully affect circulating FGF23 concentrations.…”

Section: Discussionmentioning

confidence: 99%

The metabolic bone disease associated with the Hyp mutation is independent of osteoblastic HIF1α expression

Hum

Clinkenbeard

et al. 2017

Bone Reports

View full text Add to dashboard Cite

Fibroblast growth factor-23 (FGF23) controls key responses to systemic phosphate increases through its phosphaturic actions on the kidney. In addition to stimulation by phosphate, FGF23 positively responds to iron deficiency anemia and hypoxia in rodent models and in humans. The disorder X-linked hypophosphatemia (XLH) is characterized by elevated FGF23 in concert with an intrinsic bone mineralization defect. Indeed, the Hyp mouse XLH model has disturbed osteoblast to osteocyte differentiation with altered expression of a wide variety of genes, including FGF23. The transcription factor Hypoxia inducible factor-1α (HIF1α) has been implicated in regulating FGF23 production and plays a key role in proper bone cell differentiation. Thus the goals of this study were to determine whether HIF1α activation could influence FGF23, and to test osteoblastic HIF1α production on the Hyp endocrine and skeletal phenotypes in vivo. Treatment of primary cultures of osteoblasts/osteocytes and UMR-106 cells with the HIF activator AG490 resulted in rapid HIF1α stabilization and increased Fgf23 mRNA (50–100 fold; p < 0.01–0.001) in a time- and dose-dependent manner. Next, the Phex gene deletion in the Hyp mouse was bred onto mice with a HIF1α/Osteocalcin (OCN)-Cre background. Although HIF1α effects on bone could be detected, FGF23-related phenotypes due to the Hyp mutation were independent of HIF1α in vivo. In summary, FGF23 can be driven by ectopic HIF1α activation under normal iron conditions in vitro, but factors independent of HIF1α activity after mature osteoblast formation are responsible for the disease phenotypes in Hyp mice in vivo.

show abstract

“…The effects of Fgf23 on cultured cells was often examined by the treatment of 10-100 ng/mL recombinant Fgf23, which is higher than its physiological serum levels. 17,18) Therefore, we also treated isolated macrophages with 100 ng/mL recombinant Fgf23. As LPS is known to stimulate cytokine expression in macrophages, we use LPS as a positive control.…”

Section: Fig 2 Expression Of Fgf23 In Immune Tissues and Cells (A) mentioning

confidence: 99%

Expression of Fgf23 in Activated Dendritic Cells and Macrophages in Response to Immunological Stimuli in Mice

Masuda

Ohta

Morita

et al. 2015

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Fibroblast growth factors (Fgfs) are polypeptide growth factors with diverse biological activities. While several studies have revealed that Fgf23 plays important roles in the regulation of phosphate and vitamin D metabolism, the additional physiological roles of Fgf23 remain unclear. Although it is believed that osteoblasts/osteocytes are the main sources of Fgf23, we previously found that Fgf23 mRNA is also expressed in the mouse thymus, suggesting that it might be involved in the immune system. In this study we examined the potential roles of Fgf23 in immunological responses. Mouse serum Fgf23 levels were significantly increased following inoculation with Escherichia coli or Staphylococcus aureus or intraperitoneal injection of lipopolysaccharide. We also identified activated dendritic cells and macrophages that potentially contributed to increased serum Fgf23 levels. Nuclear factor-kappa B (NF-κB) signaling was essential for the induction of Fgf23 expression in dendritic cells in response to immunological stimuli. Moreover, we examined the effects of recombinant Fgf23 protein on immune cells in vitro. Fgfr1c, a potential receptor for Fgf23, was abundantly expressed in macrophages, suggesting that Fgf23 might be involved in signal transduction in these cells. Our data suggest that Fgf23 potentially increases the number in macrophages and induces expression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine. Collectively, these data suggest that Fgf23 might be intimately involved in inflammatory processes.Key words fibroblast growth factor (Fgf); Fgf23; macrophage; dendritic cell; inflammationThe fibroblast growth factors (Fgfs) family consists of 22 polypeptide growth factors that are widely expressed in developing and adult tissues and regulate diverse biological processes, including angiogenesis, mitogenesis, cellular differentiation, and tissue repair. 1,2) Fgfs can be classified into three groups, canonical, intracellular, and hormone-like Fgfs. The canonical Fgfs bind to and activate Fgf receptors (Fgfrs) on the cell surface, resulting in the activation of several cytoplasmic signal transduction pathways. These canonical Fgfs function in a paracrine manner. The intracellular Fgfs act as intracellular signaling molecules in an Fgfr-independent manner. Hormone-like Fgfs, including Fgf15/19, Fgf21, and Fgf23, depends on Fgfrs to elicit biological responses, although they potentially function in an endocrine manner. 3) One of these hormone-like Fgfs, Fgf23, was originally identified in mice and humans by a DNA database search and was a well-known physiological regulator of phosphate and vitamin D metabolisms. [3][4][5][6] Fgf23 is produced by osteoblasts/osteocytes in response to 1,25-dihydroxyvitamine D, the biologically active form of vitamin D. 3,5,6) Secreted Fgf23 increases urinary phosphate excretion by reducing luminal expression of sodium-phosphate co-transporters in the proximal tubule. Secreted Fgf23 also attenuates systemic levels of 1,25-dihydroxyvitamine D, which stimulates phosphate...

show abstract

FGF23 Suppresses Chondrocyte Proliferation in the Presence of Soluble α-Klotho both in Vitro and in Vivo

Cited by 49 publications

References 40 publications

FGF23 Regulates Bone Mineralization in a 1,25(OH)2D3 and Klotho-Independent Manner

FGF23 Regulates Bone Mineralization in a 1,25(OH)2D3 and Klotho-Independent Manner

The metabolic bone disease associated with the Hyp mutation is independent of osteoblastic HIF1α expression

Expression of Fgf23 in Activated Dendritic Cells and Macrophages in Response to Immunological Stimuli in Mice

Contact Info

Product

Resources

About