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Acute-phase protein serum amyloid A3 is a novel paracrine coupling factor that controls bone homeostasis.
FASEB J. 2015 Apr; 29(4):1344-59.FJ

Abstract

Serum amyloid A (A-SAA/Saa3) was shown before to affect osteoblastic metabolism. Here, using RT-quantitative PCR and/or immunoblotting, we show that expression of mouse Saa3 and human SAA1 and SAA2 positively correlates with increased cellular maturation toward the osteocyte phenotype. Expression is not detected in C3H10T1/2 embryonic fibroblasts but is successively higher in preosteoblastic MC3T3-E1 cells, late osteoblastic MLO-A5 cells, and MLO-Y4 osteocytes, consistent with findings using primary bone cells from newborn mouse calvaria. Recombinant Saa3 protein functionally inhibits osteoblast differentiation as reflected by reductions in the expression of osteoblast markers and decreased mineralization in newborn mouse calvaria. Yet, Saa3 protein enhances osteoclastogenesis in mouse macrophages/monocytes based on the number of multinucleated and tartrate-resistant alkaline phosphatase-positive cells and Calcr mRNA expression. Depletion of Saa3 in MLO osteocytes results in the loss of the mature osteocyte phenotype. Recombinant osteocalcin, which is reciprocally regulated with Saa3 at the osteoblast/osteocyte transition, attenuates Saa3 expression in MLO-Y4 osteocytes. Mechanistically, Saa3 produced by MLO-Y4 osteocytes is integrated into the extracellular matrix of MC3T3-E1 osteoblasts, where it associates with the P2 purinergic receptor P2rx7 to stimulate Mmp13 expression via the P2rx7/MAPK/ERK/activator protein 1 axis. Our data suggest that Saa3 may function as an important coupling factor in bone development and homeostasis.

Authors+Show Affiliations

*Ludwig Boltzmann Institute of Osteology, Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt, Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria; and Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.*Ludwig Boltzmann Institute of Osteology, Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt, Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria; and Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.*Ludwig Boltzmann Institute of Osteology, Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt, Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria; and Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.*Ludwig Boltzmann Institute of Osteology, Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt, Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria; and Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.*Ludwig Boltzmann Institute of Osteology, Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt, Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria; and Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.*Ludwig Boltzmann Institute of Osteology, Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt, Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria; and Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.*Ludwig Boltzmann Institute of Osteology, Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt, Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria; and Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA.*Ludwig Boltzmann Institute of Osteology, Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt, Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria; and Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA vanwijnen.andre@mayo.edu franz.varga@osteologie.at.*Ludwig Boltzmann Institute of Osteology, Wiener Gebietskrankenkasse and Allgemeine Unfallversicherungsanstalt, Trauma Center Meidling, 1st Medical Department, Hanusch Hospital, Vienna, Austria; and Departments of Orthopedic Surgery and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA vanwijnen.andre@mayo.edu franz.varga@osteologie.at.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25491310

Citation

Thaler, Roman, et al. "Acute-phase Protein Serum Amyloid A3 Is a Novel Paracrine Coupling Factor That Controls Bone Homeostasis." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 29, no. 4, 2015, pp. 1344-59.
Thaler R, Sturmlechner I, Spitzer S, et al. Acute-phase protein serum amyloid A3 is a novel paracrine coupling factor that controls bone homeostasis. FASEB J. 2015;29(4):1344-59.
Thaler, R., Sturmlechner, I., Spitzer, S., Riester, S. M., Rumpler, M., Zwerina, J., Klaushofer, K., van Wijnen, A. J., & Varga, F. (2015). Acute-phase protein serum amyloid A3 is a novel paracrine coupling factor that controls bone homeostasis. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 29(4), 1344-59. https://doi.org/10.1096/fj.14-265512
Thaler R, et al. Acute-phase Protein Serum Amyloid A3 Is a Novel Paracrine Coupling Factor That Controls Bone Homeostasis. FASEB J. 2015;29(4):1344-59. PubMed PMID: 25491310.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acute-phase protein serum amyloid A3 is a novel paracrine coupling factor that controls bone homeostasis. AU - Thaler,Roman, AU - Sturmlechner,Ines, AU - Spitzer,Silvia, AU - Riester,Scott M, AU - Rumpler,Monika, AU - Zwerina,Jochen, AU - Klaushofer,Klaus, AU - van Wijnen,Andre J, AU - Varga,Franz, Y1 - 2014/12/09/ PY - 2014/10/01/received PY - 2014/11/17/accepted PY - 2014/12/11/entrez PY - 2014/12/11/pubmed PY - 2015/6/24/medline KW - osteoblast KW - osteoclast KW - osteocyte KW - osteogenesis SP - 1344 EP - 59 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J. VL - 29 IS - 4 N2 - Serum amyloid A (A-SAA/Saa3) was shown before to affect osteoblastic metabolism. Here, using RT-quantitative PCR and/or immunoblotting, we show that expression of mouse Saa3 and human SAA1 and SAA2 positively correlates with increased cellular maturation toward the osteocyte phenotype. Expression is not detected in C3H10T1/2 embryonic fibroblasts but is successively higher in preosteoblastic MC3T3-E1 cells, late osteoblastic MLO-A5 cells, and MLO-Y4 osteocytes, consistent with findings using primary bone cells from newborn mouse calvaria. Recombinant Saa3 protein functionally inhibits osteoblast differentiation as reflected by reductions in the expression of osteoblast markers and decreased mineralization in newborn mouse calvaria. Yet, Saa3 protein enhances osteoclastogenesis in mouse macrophages/monocytes based on the number of multinucleated and tartrate-resistant alkaline phosphatase-positive cells and Calcr mRNA expression. Depletion of Saa3 in MLO osteocytes results in the loss of the mature osteocyte phenotype. Recombinant osteocalcin, which is reciprocally regulated with Saa3 at the osteoblast/osteocyte transition, attenuates Saa3 expression in MLO-Y4 osteocytes. Mechanistically, Saa3 produced by MLO-Y4 osteocytes is integrated into the extracellular matrix of MC3T3-E1 osteoblasts, where it associates with the P2 purinergic receptor P2rx7 to stimulate Mmp13 expression via the P2rx7/MAPK/ERK/activator protein 1 axis. Our data suggest that Saa3 may function as an important coupling factor in bone development and homeostasis. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/25491310/Acute_phase_protein_serum_amyloid_A3_is_a_novel_paracrine_coupling_factor_that_controls_bone_homeostasis_ L2 - http://www.fasebj.org/doi/full/10.1096/fj.14-265512?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -