α2-HS Glycoprotein/Fetuin, a Transforming Growth Factor-β/Bone Morphogenetic Protein Antagonist, Regulates Postnatal Bone Growth and Remodeling

Szweras, Melanie; Liu, Danmei; Partridge, Emily A.; Pawling, Judy; Sukhu, Balram; Clokie, Cameron M. L.; Jahnen-Dechent, Willi; Tenenbaum, Howard C.; Swallow, Carol J.; Grynpas, Marc D.; Dennis, James W.

doi:10.1074/jbc.m112234200

Cited by 201 publications

(155 citation statements)

References 56 publications

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“…The IHC localization of fetuin-A in the mineralized areas of bone matrix has been already described in normal adult humans [28] and other mammals [29,30]. Our results show that the protein is highly represented in mineralized matrix of normal bone of uremic patients, as well as in any form of renal osteodystrophy, independent of the rate of bone turnover and of the type (lamellar or woven) of bone structure.…”

Section: Discussionsupporting

confidence: 74%

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

et al. 2009

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Matrix Gla protein (MGP) and fetuin-A are inhibitors of arterial calcifications. In blood of rats, calcium-phosphate-fetuin-MGP complexes, produced in bone, have been identified. Indeed, an association between bone resorption, release of such complexes, and arterial calcifications has been reported. We have investigated the synthesis and localization of fetuin-A and MGP in bone of hemodialysis patients and the possible contribution of bone cells in arterial calcifications. Bone biopsies from 11 hemodialysis patients were used for histology, in situ hybridization of fetuin-A and MGP messenger RNA (mRNA), immunohistochemistry of fetuin-A, and total, carboxylated, and non-carboxylated MGP proteins. Patients showed various types of renal osteodystrophy, or normal bone. MGP was synthesized and expressed (total and carboxylated) by osteoblasts, osteocytes, and most osteoclasts, while fetuin-A by osteoblasts and osteocytes. Fetuin-A and carboxylated MGP proteins were positive in the calcified matrix, while total MGP was negative. Osteoid seams were negative to fetuin-A, lightly positive to carboxylated MGP, and occasionally positive to total MGP. Undercarboxylated MGP was mostly undetectable. In adult humans, fetuin-A is produced also by osteoblasts, and not only by hepatocytes, as previously believed. MGP, essentially carboxylated, is synthesized by osteoblasts and most osteoclasts. Increased bone turnover can be an important contributor to arterial calcifications.

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Section: Discussionsupporting

confidence: 74%

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

et al. 2009

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“…Moreover, it has been suggested that fetuin-A is a transforming growth factor-β type II receptor mimic and acts as an antagonist of TGF-β and TGF-β-related bone morphogenetic protein (BMP) activities (27). Multiple investigations of fetuin-A-deficient mice on various genetic backgrounds suggest that fetuin-A has a role as a systemically acting inhibitor of ectopic bone formation (28)(29)(30)(31). Bone lesions in prostate cancer are predominantly osteoblastic and cause a relative increase in bone deposition (32).…”

Section: Discussionmentioning

confidence: 99%

Discovery and horizontal follow-up of an autoantibody signature in human prostate cancer

Mintz¹,

Rietz

Cardó-Vila

et al. 2015

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

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In response to an urgent need for improved diagnostic and predictive serum biomarkers for management of metastatic prostate cancer, we used phage display fingerprinting to analyze sequentially acquired serum samples from a patient with advancing prostate cancer. We identified a peptide ligand, CTFAGSSC, demonstrating an increased recovery frequency over time. Serum antibody reactivity to this peptide epitope increased in the index patient, in parallel with development of deteriorating symptoms. The antigen mimicking the peptide epitope was identified as alpha-2-HeremansSchmid glycoprotein, also known as fetuin-A. Metastatic prostate cancer cell lines and bone metastasis samples displayed robust fetuin-A expression, and we demonstrated serum immune reactivity to fetuin-A with concomitant development of metastatic castrateresistant disease in a large cohort of prostate cancer patients. Whereas fetuin-A is an established tumor antigen in several types of cancer, including breast cancer, glioblastoma, and pancreas cancer, this report is to our knowledge the first study implicating fetuin-A in prostate cancer and indicating that autoantibodies specific for fetuin-A show utility as a prognostic indicator for prostate cancer patients prone to progress to metastatic disease.cancer biomarker | peptide library | prostate cancer | phage display

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“…39 Fetuin A is also involved in the regulation of osteogenesis and bone resorption. 99 Clinical studies consistently show that fetuin-A deficiency is associated with vascular calcification and mortality in chronic kidney disease patients. Both chronic inflammation and uremia may contribute to fetuin-A depletion, 98 and low fetuin-A serum concentrations in hemodialysis patients are associated with severe extraosseous calcifications and highly increased cardiovascular mortality.…”

Section: Discussionmentioning

confidence: 99%

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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α2-HS Glycoprotein/Fetuin, a Transforming Growth Factor-β/Bone Morphogenetic Protein Antagonist, Regulates Postnatal Bone Growth and Remodeling

Cited by 201 publications

References 56 publications

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

Discovery and horizontal follow-up of an autoantibody signature in human prostate cancer

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

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