Specific ablation of mouse Fam20C in cells expressing type I collagen leads to skeletal defects and hypophosphatemia

Abstract

FAM20C mutations in humans cause Raine syndrome and our previous studies showed that global inactivation of mouse Fam20C led to bone and dental defects. By crossbreeding 2.3 kb Col 1a1-Cre mice with Fam20C flox/flox mice, we created 2.3 kb Col 1a1-Cre;Fam20C foxl/flox (cKO) mice, in which Fam20C was inactivated in cells expressing Type I collagen. This study showed that the long bones of cKO mice were shorter and had a lower level of mineralization compared to the normal mice. The collagen fibrils in Fam20C-deficient bone were disorganized and thicker while the growth plate cartilage in cKO mice was disorganized and wider compared to the normal mice. The Fam20C-deficient bone had a lower level of dentin matrix protein 1, and higher levels of osteopontin and bone sialoprotein than the normal. The blood of cKO mice had an elevated level of fibroblast growth factor 23 and reduced level of phosphorus. These findings indicate that inactivation of Fam20C in cells expressing type I collagen led to skeletal defects and hypophosphatemia. The altered levels of dentin matrix protein 1 and osteopontin in Fam20C-deficient bone may be significant contributors to the mineralized tissue defects in human patients and animals suffering from the functional loss of FAM20C.

A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age

“…In case of inherited hypophosphatemia, hypophosphatemia and rickets develop after birth following cessation of transplacental phosphate transport, which is also evident in a few RS cases studied shortly after birth [31]. In line with that, undermineralization, but not osteosclerosis, had been detected in conditional Fam20c knockout mice in older ages [10,41]. However, all reported cases with generalized osteosclerosis in RS were detected at birth or shortly after birth.…”

Osteocytic FGF23 and Its Kidney Function

“…In contrast to the O -glycosylation induced by GALNT3 which stabilizes FGF23, the phosphorylation at position S 180 by the kinase FAM20C inhibited O -glycosylation of FGF23, thus promoting FGF23 cleavage ( 98 ) ( Figure 2 ). Indeed, recessive inactivating mutations in human FAM20C cause ARHR type 3 (ARHR3; Raines syndrome), consistent with its role as an FGF23 de-stabilizer ( 100 , 101 ).…”

Two Novel FAM20C Variants in a Family with Raine Syndrome

“…SIBLING proteins include OPN, DMP1, BSP, extracellular MEPE, and DSPP. Other proteins include specific extracellular matrix and transport proteins, proteases and protease inhibitors, plus biologically active peptide hormones, which regulate calcium phosphate precipitation as hydroxyapatite as well as BMP4 (Bone morphogenetic protein 4), which has a role in osteoclast differentiation and maturation [19,20,[61][62][63][64].…”

“…They participate in processes that include wound healing, lipid homeostasis, endopeptidase inhibitory activity, adhesion and cell migration, and they also appear to be involved in cancer [14][15][16][17]. FAM20C role in the biomineralization process occurs through phosphorylation of members of the secretory calcium-binding phosphoproteins (SCPP) family, which include the small integrin-binding ligand N-linked glycoprotein (SIBLING proteins), such as dentin matrix proteins (DMP1), bone sialoprotein (BSP), osteopontin (OPN), matrix extracellular phosphoglycoprotein (MEPE), and dentine sialophosphoprotein (DSPP) [15,[18][19][20]. Moreover, FAM20C regulates fibroblast growth factor 23 (FGF23) secreted by osteoblasts and osteocytes, which plays a major role in the renal metabolism of phosphate, in the reabsorption of phosphate and the catabolism of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) [21,22].…”