Expression of FAM20C in the Osteogenesis and Odontogenesis of Mouse

Wang, Xiaofang; Hao, Jianjun; Xie, Yixia; Sun, Yao; Hernandez, Brianda; Yamoah, Albert K.; Prasad, Monica; Zhu, Qinglin; Feng, Jian Q.; Qin, Chunlin

doi:10.1369/jhc.2010.956565

Cited by 62 publications

(79 citation statements)

References 13 publications

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“…The periosteal proliferation and lysis of tooth roots, cementum, and periodontal bone were mostly due the periapical inflammation and necrosis extending from the pulp cavity, although a role for primary defects in these locations cannot be ruled out given the reported expression of FAM20C in ameloblasts, odontoblasts, cementoblasts, and periodontal ligament fibroblasts. 108 The markedly thickened maxillae and mandibles were a prominent feature in Fam20c -/-mice and mirrored similar changes in other bones throughout the body, where trabeculae were outlined by broad bands of osteoid.…”

Section: Discussionmentioning

confidence: 78%

“…86 The localization of FAM20C in the matrices of dentin, enamel, and alveolar bone suggests that it is an extracellular matrix protein. 108 Mutations in FAM20C have been linked to Raine syndrome in humans, an osteosclerotic bone dysplasia, proving a role for FAM20C protein in bone development and mineralization. 36, 86 Raine syndrome is accompanied by increased periosteal bone formation and facial dysmorphism.…”

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confidence: 99%

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Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

et al. 2012

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The FAM20 family of secreted proteins consists of three members (FAM20A, FAM20B, and FAM20C) recently linked to developmental disorders suggesting roles for FAM20 proteins in modulating biomineralization processes. The authors report here findings in knockout mice having null mutations affecting each of the three FAM20 proteins. Both Fam20a and Fam20c null mice survived to adulthood and showed biomineralization defects. Fam20b -/-embryos showed severe stunting and increased mortality at E13.5, although early lethality precluded detailed investigations. Physiologic calcification or biomineralization of extracellular matrices is a normal process in the development and functioning of various tissues (eg, bones and teeth). The lesions that developed in teeth, bones, or blood vessels after functional deletion of either Fam20a or Fam20c support a significant role for their encoded proteins in modulating biomineralization processes. Severe amelogenesis imperfecta (AI) was present in both Fam20a and Fam20c null mice. In addition, Fam20a-/-mice developed disseminated calcifications of muscular arteries and intrapulmonary calcifications, similar to those of fetuin-A deficient mice, although they were normocalcemic and normophosphatemic, with normal dentin and bone. Fam20a gene expression was detected in ameloblasts, odontoblasts, and the parathyroid gland, with local and systemic effects suggesting both local and/or systemic effects for FAM20A. In contrast, Fam20c-/-mice lacked ectopic calcifications but were severely hypophosphatemic and developed notable lesions in both dentin and bone to accompany the AI. The bone and dentin lesions, plus the marked hypophosphatemia and elevated serum alkaline phosphatase and FGF23 levels, are indicative of autosomal recessive hypophosphatemic rickets/osteomalacia in Fam20c -/-mice.Keywords amelogenesis imperfecta, knockout, rickets, phosphatonin, ectopic mineralization, biomineralization, dentin, osteomalacia, osteosclerosisThe FAM20 family of secreted proteins in mammals consists of three members (FAM20A, FAM20B, and FAM20C) that were initially thought to have roles in regulating the differentiation and function of hematopoietic and other tissues. 65 Since then, there have been reports linking mutations in both FAM20A and FAM20C to developmental disorders involving bones and/or teeth, suggesting a role for FAM20 proteins in modulating biomineralization processes. In humans, a mutation in FAM20A was recently linked to the occurrence of amelogenesis imperfecta and gingival hyperplasia in a consanguineous family. 69 However, lesions were not reported in bones or teeth of transgenic mice with a partial deletion of Fam20a, and their stunted growth was attributed to malnutrition and an unspecified metabolic disorder. 4 To the best of our knowledge, there have been only two reports elucidating the function FAM20B, which was shown to be a kinase that phosphorylates glycosaminoglycans 50 and in vivo to be involved in cartilage matrix production and skeletal development in zebrafish. 2...

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Section: Discussionmentioning

confidence: 78%

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confidence: 99%

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

et al. 2012

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“…Biochemical analysis of the patients' sera identified elevated intact FGF23. Because FGF23 is expressed in tissues that show high levels of Fam20C expression (30) and contains Fam20C consensus S-x-E/pS motifs (Fig. 1A), we hypothesized that Fam20C may directly regulate FGF23 by phosphorylation.…”

Section: Fgf23mentioning

confidence: 99%

Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis

Tagliabracci¹,

Engel²,

Wiley³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

271

252

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The family with sequence similarity 20, member C (Fam20C) has recently been identified as the Golgi casein kinase. Fam20C phosphorylates secreted proteins on Ser-x-Glu/pSer motifs and loss-of-function mutations in the kinase cause Raine syndrome, an often-fatal osteosclerotic bone dysplasia. Fam20C is potentially an upstream regulator of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23), because humans with FAM20C mutations and Fam20C KO mice develop hypophosphatemia due to an increase in full-length, biologically active FGF23. However, the mechanism by which Fam20C regulates FGF23 is unknown. Here we show that Fam20C directly phosphorylates FGF23 on Ser 180 , within the FGF23 R 176 XXR 179 /S 180 AE subtilisin-like proprotein convertase motif. This phosphorylation event inhibits O-glycosylation of FGF23 by polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-T3), and promotes FGF23 cleavage and inactivation by the subtilisin-like proprotein convertase furin. Collectively, our results provide a molecular mechanism by which FGF23 is dynamically regulated by phosphorylation, glycosylation, and proteolysis. Furthermore, our findings suggest that cross-talk between phosphorylation and O-glycosylation of proteins in the secretory pathway may be an important mechanism by which secreted proteins are regulated.phosphate homeostasis | rickets | Fam20 | familial tumoral calcinosis | chronic kidney disease P rotein kinases are evolutionarily conserved enzymes that regulate numerous cellular processes by transferring a molecule of phosphate from ATP to target substrates (1, 2). The vast majority of theses enzymes function within the nucleus and cytosol. In contrast, there are several examples of phosphorylated proteins that are secreted from the cell, which raises the question: What are the kinases that phosphorylate these secreted phosphoproteins? We recently identified a small family of secretory pathway kinases that phosphorylate secreted proteins and proteoglycans (3). These enzymes have N-terminal signal sequences that direct them to the lumen of the endoplasmic reticulum, where they encounter the proteins or proteoglycans that they phosphorylate. One member of this atypical kinase family is the family with sequence similarity 20, member C (Fam20C), which phosphorylates secreted proteins on Ser(S)-xGlu(E)/pSer(pS) (S-x-E/pS) motifs (3, 4). Because Fam20C localizes within the secretory pathway and the vast majority of secreted phosphoproteins are phosphorylated on S-x-E/pS motifs, Fam20C has been proposed to play a major role in the generation of the secreted phosphoproteome (5-7). For example, ∼75% of human serum and cerebrospinal fluid phosphoproteins are phosphorylated on S-x-E/pS motifs (8, 9). This includes proteins important for tooth and bone formation, as well as numerous hormones. In most cases, the functional importance of these phosphorylation events is unknown.Loss-of-function mutations in the human FAM20C gene cause Raine syndrome, an often-fatal osteosclerotic bone dysplasia (10, 11)....

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“…Thus, interruption of the signaling in one tissue may cause abnormalities in the other. Analysis of our previous data indicated that FAM20C is expressed in both ameloblasts and odontoblasts (Wang et al 2010);Sox2-Cre;Fam20C fl/fl mice, in which Fam20C was ubiquitously inactivated, had both dentin and enamel defects, as well as hypophosphatemic rickets. It remains to be determined if the enamel and dentin defects in the Fam20C-cKO mice are correlated with, or independent of, each other, and if hypophosphatemia contributes to the dental defects, since phosphate composes the major content of hydroxylapatite in both dentin and enamel.…”

Section: Introductionmentioning

confidence: 97%

The Specific Role of FAM20C in Dentinogenesis

Wang

Liu

et al. 2014

J Dent Res

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FAM20C is an evolutionarily reserved molecule highly expressed in mineralized tissues. Previously we demonstrated that Sox2-Cre;Fam20C fl/fl mice, in which Fam20C was ubiquitously inactivated, had dentin and enamel defects as well as hypophosphatemic rickets. We also showed that K14-Cre;Fam20C fl/fl mice, in which Fam20C was specifically inactivated in the epithelium, had enamel defects but lacked hypophosphatemia and defects in the bone and dentin. These results indicated that the enamel defects in the Sox2-Cre;Fam20C fl/fl mice were independent of dentin defects and hypophosphatemia. To determine if the dentin defects in the Sox2-Cre;Fam20C fl/fl mice were associated with the enamel defects and hypophosphatemia, we crossed mice showed remarkable dentin and alveolar bone defects, while their enamel did not show apparent defects. The serum FGF23 levels in these mice were higher than normal but lower than those in the Sox2-Cre;Fam20C fl/fl mice; they developed a mild type of hypophosphatemia that did not cause major defects in long bones. These results indicate that the dentin defects in the Sox2-Cre;Fam20C fl/fl mice were independent of the enamel defects.

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Expression of FAM20C in the Osteogenesis and Odontogenesis of Mouse

Cited by 62 publications

References 13 publications

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

Amelogenesis Imperfecta and Other Biomineralization Defects in Fam20a and Fam20c Null Mice

Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis

The Specific Role of FAM20C in Dentinogenesis

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