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

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1344-1359
Number of pages16
JournalFASEB Journal
Volume29
Issue number4
DOIs
StatePublished - Apr 1 2015

Fingerprint

Osteocytes
Acute-Phase Proteins
Osteoblasts
Amyloid
Bone
Homeostasis
Bone and Bones
Serum
Purinergic P2 Receptors
Serum Amyloid A Protein
Recombinant proteins
Macrophages
Osteocalcin
Skull
Transcription Factor AP-1
Fibroblasts
Metabolism
Alkaline Phosphatase
Phenotype
Cells

Keywords

  • Osteoblast
  • Osteoclast
  • Osteocyte
  • Osteogenesis

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Thaler, R., Sturmlechner, I., Spitzer, S., Riester, S. M., Rumpler, M., Zwerina, J., ... Varga, F. (2015). Acute-phase protein serum amyloid A3 is a novel paracrine coupling factor that controls bone homeostasis. FASEB Journal, 29(4), 1344-1359. https://doi.org/10.1096/fj.14-265512

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; van Wijnen, Andre J; Varga, Franz.

In: FASEB Journal, Vol. 29, No. 4, 01.04.2015, p. 1344-1359.

Research output: Contribution to journalArticle

Thaler, R, Sturmlechner, I, Spitzer, S, Riester, SM, Rumpler, M, Zwerina, J, Klaushofer, K, van Wijnen, AJ & Varga, F 2015, 'Acute-phase protein serum amyloid A3 is a novel paracrine coupling factor that controls bone homeostasis', FASEB Journal, vol. 29, no. 4, pp. 1344-1359. https://doi.org/10.1096/fj.14-265512
Thaler R, Sturmlechner I, Spitzer S, Riester SM, Rumpler M, Zwerina J et al. Acute-phase protein serum amyloid A3 is a novel paracrine coupling factor that controls bone homeostasis. FASEB Journal. 2015 Apr 1;29(4):1344-1359. https://doi.org/10.1096/fj.14-265512
Thaler, Roman ; Sturmlechner, Ines ; Spitzer, Silvia ; Riester, Scott M. ; Rumpler, Monika ; Zwerina, Jochen ; Klaushofer, Klaus ; van Wijnen, Andre J ; Varga, Franz. / Acute-phase protein serum amyloid A3 is a novel paracrine coupling factor that controls bone homeostasis. In: FASEB Journal. 2015 ; Vol. 29, No. 4. pp. 1344-1359.
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