Acute‐phase protein serum amyloid A3 is a novel paracrine coupling factor that controls bone homeostasis

Thaler, Roman; Sturmlechner, Ines; Spitzer, Silvia; Riester, Scott M.; Rumpler, Monika; Zwerina, Jochen; Klaushofer, Klaus; Wijnen, André J. van; Varga, Franz

doi:10.1096/fj.14-265512

Cited by 28 publications

(28 citation statements)

References 69 publications

(113 reference statements)

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“…Previous studies suggest that osteosarcomas may secrete putative secreted tumor markers like serum amyloid A1/(SAA1), Ezrin/EZR, and Transthyretin/TTR [Li et al, , ]. The detection of human SAA1 is particularly intriguing because the functional mouse equivalent (i.e., Saa3), known to be produced by osteoblast‐lineage cells and osteocytes, promotes osteoclastogenesis [Thaler et al, ]. Previous proteomic studies analysed serum samples, whereas our study analyzed proteins directly secreted by osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Exosomes and Exosome-Free Conditioned Media From Human Osteosarcoma Cell Lines Reveals Secretion of Proteins Related to Tumor Progression

et al. 2016

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Osteosarcomas are the most prevalent bone tumors in pediatric patients, but can also occur later in life. Bone tumors have the potential to metastasize to lung and occasionally other vital organs. To understand how osteosarcoma cells interact with their micro-environment to support bone tumor progression and metastasis, we analyzed secreted proteins and exosomes from three human osteosarcoma cell lines. Exosome isolation was validated by transmission electron microscopy (TEM) and immuno-blotting for characteristic biomarkers (CD63, CD9, and CD81). Exosomal and soluble proteins (less than 100 kDa) were identified by mass spectrometry analysis using nanoLC-MS/MS and classified by functional gene ontology clustering. We identified a secretome set of >3,000 proteins for both fractions, and detected proteins that are either common or unique among the three osteosarcoma cell lines. Protein ontology comparison of proteomes from exosomes and exosome-free fractions revealed differences in the enrichment of functional categories associated with different biological processes, including those related to tumor progression (i.e., angiogenesis, cell adhesion, and cell migration). The secretome characteristics of osteosarcoma cells are consistent with the pathological properties of tumor cells with metastatic potential. J. Cell. Biochem. 118: 351-360, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Exosomes and Exosome-Free Conditioned Media From Human Osteosarcoma Cell Lines Reveals Secretion of Proteins Related to Tumor Progression

et al. 2016

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“…Saa3 serves as an endogenous ligand for TLR4 that facilitates lung tumor metastasis (Hiratsuka et al, 2008). It also functions as a paracrine factor for bone homeostasis (Thaler et al, 2015). A recent study implies that Saa3 signaling through TLR2 contributes to an enhanced suppressive capacity of myeloid-derived suppressor cells, thus exacerbating tumor growth (Lee et al, 2014).…”

Section: Saa In Other Speciesmentioning

confidence: 99%

Serum amyloid A1: Structure, function and gene polymorphism

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2016

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Inducible expression of serum amyloid A (SAA) is a hallmark of the acute-phase response, which is a conserved reaction of vertebrates to environmental challenges such as tissue injury, infection and surgery. Human SAA1 is encoded by one of the four SAA genes and is the best-characterized SAA protein. Initially known as a major precursor of amyloid A (AA), SAA1 has been found to play an important role in lipid metabolism and contributes to bacterial clearance, the regulation of inflammation and tumor pathogenesis. SAA1 has five polymorphic coding alleles (SAA1.1 – SAA1.5) that encode distinct proteins with minor amino acid substitutions. Single nucleotide polymorphism (SNP) has been identified in both the coding and non-coding regions of human SAA1. Despite high levels of sequence homology among these variants, SAA1 polymorphisms have been reported as risk factors of cardiovascular diseases and several types of cancer. A recently solved crystal structure of SAA1.1 reveals a hexameric bundle with each of the SAA1 subunits assuming a 4-helix structure stabilized by the C-terminal tail. Analysis of the native SAA1.1 structure has led to the identification of a competing site for high-density lipoprotein (HDL) and heparin, thus providing the structural basis for a role of heparin and heparan sulfate in the conversion of SAA1 to AA. In this brief review, we compares human SAA1 with other forms of human and mouse SAAs, and discuss how structural and genetic studies of SAA1 have advanced our understanding of the physiological functions of the SAA proteins.

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“…parathyroid hormone, bone morphogenetic proteins, and winglesstype murine mammary tumor virus integration site family members (WNTs)), bone-resorbing osteoclasts (e.g. RANKL 4 / TNSF11), or both such as members of the serum amyloid A family (6,7). Both cell types are targeted by a number of different therapeutic approaches that counteract bone degeneration in aging patients and other disorders provoking bone loss.…”

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Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Thaler

Maurizi

Roschger

et al. 2016

Journal of Biological Chemistry

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Bone degenerative pathologies like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Here we show that sulforaphane (SFN), a naturally occurring isothiocyanate, promotes osteoblast differentiation by epigenetic mechanisms. SFN enhances active DNA demethylation via Tet1 and Tet2 and promotes preosteoblast differentiation by enhancing extracellular matrix mineralization and the expression of osteoblastic markers (Runx2, Col1a1, Bglap2, Sp7, Atf4, and Alpl). SFN decreases the expression of the osteoclast activator receptor activator of nuclear factor-B ligand (RANKL) in osteocytes and mouse calvarial explants and preferentially induces apoptosis in preosteoclastic cells via up-regulation of the Tet1/Fas/Caspase 8 and Caspase 3/7 pathway. These mechanistic effects correlate with higher bone volume (ϳ20%) in both normal and ovariectomized mice treated with SFN for 5 weeks compared with untreated mice as determined by microcomputed tomography. This effect is due to a higher trabecular number in these mice. Importantly, no shifts in mineral density distribution are observed upon SFN treatment as measured by quantitative backscattered electron imaging. Our data indicate that the food-derived compound SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, shifting the balance of bone homeostasis and favoring bone acquisition and/or mitigation of bone resorption in vivo. Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis.

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Acute‐phase protein serum amyloid A3 is a novel paracrine coupling factor that controls bone homeostasis

Cited by 28 publications

References 69 publications

Proteomic Analysis of Exosomes and Exosome-Free Conditioned Media From Human Osteosarcoma Cell Lines Reveals Secretion of Proteins Related to Tumor Progression

Proteomic Analysis of Exosomes and Exosome-Free Conditioned Media From Human Osteosarcoma Cell Lines Reveals Secretion of Proteins Related to Tumor Progression

Serum amyloid A1: Structure, function and gene polymorphism

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

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