Yoshihiro Tamamura, Kenta Terai and Akira Yamaguchi : Notch signaling modulates Fgf23 expression through crosstalk with hypoxia and PTH pathways in osteogenic cells., Molecular and Cellular Endocrinology, 610, 2025.
2.
Ziyang Liu, Zhifeng He, Linan Shi, Tomoki Mori, Yoshihiro Tamamura, Nobuyuki Udagawa and Yuko Nakamichi : Vitamin D receptor in osteoblast lineage cells mediates increased sclerostin circulation and decreased bone formation in hypervitaminosis D, The Journal of Steroid Biochemistry and Molecular Biology, 249, 106711, 2025.
(要約)
Hypervitaminosis D is induced iatrogenically or endogenously. We previously reported that the vitamin D receptor (VDR) in osteoblast lineage cells mediates bone resorption and soft-tissue calcification in hypervitaminosis D. However, bone formation in hypervitaminosis D remains understudied. Here, we show that abundant 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] suppresses bone formation through VDR in osteoblast lineage cells. High-dose 1,25(OH)2D3 suppressed bone formation and increased serum sclerostin, a bone formation inhibitor, in Control but not osteoblast lineage-specific VDR-cKO [Osterix (Osx)-VDR-cKO] mice. However, Sost mRNA expression in bone was downregulated by 1,25(OH)2D3 in Control but not Osx-VDR-cKO mice. Meanwhile, mRNA expression of β-1,4-N-acetyl-galactosaminyltransferase 3 (B4GALNT3), whose function is reported to decrease circulating sclerostin, was suppressed by 1,25(OH)2D3 in bone in Control but not Osx-VDR-cKO mice. Overexpressed B4galnt3 in rodent osteoblast-lineage cell lines increased GalNAcβ1→4GlcNAc- (LDN-) glycosylated sclerostin, suggesting that this modification can explain the discordance between serum sclerostin levels and mRNA in bone. Although excessive 1,25(OH)2D3 increased mRNA levels of Fibroblast growth factor 23 (Fgf23), another osteotropic factor, by 10-fold through VDR in osteoblast lineage cells, it was previously shown to increase serum FGF23 levels by several hundred-fold. 1,25(OH)2D3-induced changes of FGF23-degradation regulators, such as furin, polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), and family with sequence similarity member 20 C (FAM20C), did not match the markedly high FGF23 levels, suggesting the existence of other regulators of FGF23. These findings suggest that VDR plays pivotal roles in the suppression of bone formation in hypervitaminosis D, possibly by increasing circulations of sclerostin and FGF23 through post-translational or post-transcriptional mechanisms.
(キーワード)
B4GALNT3 / Bone formation / FGF23 / Hypervitaminosis D / Osterix-VDR-cKO mice / Sclerostin / Vitamin D receptor
Yoshihiro Tamamura, Kei Sakamoto, Ken-Ichi Katsube and Akira Yamaguchi : Notch signaling is involved in Fgf23 upregulation in osteocytes., Biochemical and Biophysical Research Communications, 2019.
(要約)
Fgf23 acts as a phosphaturic factor secreted from osteocytes in bone, but the mechanism regulating Fgf23 is not fully understood. Here, we showed the colocalization of Fgf23, Notch, and Hes1, a downstream target of Notch signaling, in numerous osteocytes in cortical bone of femur in wild-type mice. We generated NICD (Notch intracellular domain)-transgenic mice driven by a 2.3 kb collagenα1 (I) (Col1a1) promoter fragment. Western blot and RT-PCR analyses revealed upregulation of Notch protein and mRNA levels in the bones of transgenic mice compared with those in wild-type mice. In the transgenic mice, immunohistochemical studies demonstrated that numerous osteocytes and osteoblasts express Notch in the rib, whereas only osteoblasts exhibit Notch in the femur. NICD-transgenic mice were characterized by upregulation of Fgf23 mRNA levels in the rib but not in the femur compared with that in wild type mice. These mice exhibited dwarfism associated with an osteomalacia phenotype. The expression of Alpl, Col1a1, and Bglap decreased in NICD-transgenic mice compared with wild-type mice. UMR-106 cells cultured on Jagged1-immobilized wells significantly increased Fgf23 expressions associating with upregulation of Hes1 and Hey1. These results imply that Notch signaling is a positive regulator for Fgf23 expression in osteocytes.
A Yamashita, Yoshihiro Tamamura, M Morioka, P Karagiannis, N Shima and N Tsumaki : Considerations in hiPSC-derived cartilage for articular cartilage repair, Inflammation and Regeneration, 38, 17, 1-7, 2018.
(要約)
A lack of cell or tissue sources hampers regenerative medicine for articular cartilage damage. We review and discuss the possible use of pluripotent stem cells as a new source for future clinical use. Human induced pluripotent stem cells (hiPSCs) have several advantages over human embryonic stem cells (hESCs). Methods for the generation of chondrocytes and cartilage from hiPSCs have been developed. To reduce the cost of this regenerative medicine, allogeneic transplantation is preferable. hiPSC-derived cartilage shows low immunogenicity like native cartilage, because the cartilage is avascular and chondrocytes are segregated by the extracellular matrix. In addition, we consider our experience with the aberrant deposition of lipofuscin or melanin on cartilage during the chondrogenic differentiation of hiPSCs. Cartilage generated from allogeneic hiPSC-derived cartilage can be used to repair articular cartilage damage.