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PMID:16149051

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Citation

Bodine, PV, Billiard, J, Moran, RA, Ponce-de-Leon, H, McLarney, S, Mangine, A, Scrimo, MJ, Bhat, RA, Stauffer, B, Green, J, Stein, GS, Lian, JB and Komm, BS (2005) The Wnt antagonist secreted frizzled-related protein-1 controls osteoblast and osteocyte apoptosis. J. Cell. Biochem. 96:1212-30

Abstract

Mechanisms controlling human bone formation remain to be fully elucidated. We have used differential display-polymerase chain reaction analysis to characterize osteogenic pathways in conditionally immortalized human osteoblasts (HOBs) representing distinct stages of differentiation. We identified 82 differentially expressed messages and found that the Wnt antagonist secreted frizzled-related protein (sFRP)-1 was the most highly regulated of these. Transient transfection of HOBs with sFRP-1 suppressed canonical Wnt signaling by 70% confirming its antagonistic function in these cells. Basal sFRP-1 mRNA levels increased 24-fold during HOB differentiation from pre-osteoblasts to pre-osteocytes, and then declined in mature osteocytes. This expression pattern correlated with levels of cellular viability such that the pre-osteocytes, which had the highest levels of sFRP-1 mRNA, also had the highest rate of cell death. Basal sFRP-1 mRNA levels also increased 29-fold when primary human mesenchymal stem cells were differentiated to osteoblasts supporting the developmental regulation of the gene. Expression of sFRP-1 mRNA was induced 38-fold following prostaglandin E2 (PGE2) treatment of pre-osteoblasts and mature osteoblasts that had low basal message levels. In contrast, sFRP-1 expression was down-regulated by as much as 80% following transforming growth factor (TGF)-beta1 treatment of pre-osteocytes that had high basal mRNA levels. Consistent with this, treatment of pre-osteoblasts and mature osteoblasts with PGE(2) increased apoptosis threefold, while treatment of pre-osteocytes with TGF-beta1 decreased cell death by 50%. Likewise, over-expression of sFRP-1 in HOBs accelerated the rate of cell death threefold. These results establish sFRP-1 as an important negative regulator of human osteoblast and osteocyte survival.

Links

PubMed Online version:10.1002/jcb.20599

Keywords

Animals; Annexin A5/metabolism; Annexin A5/pharmacology; Apoptosis/drug effects; Apoptosis/physiology; Cell Differentiation/drug effects; Cells, Cultured; Dinoprostone/metabolism; Dinoprostone/pharmacology; Gene Expression Regulation/drug effects; Humans; In Situ Hybridization; Mice; Osteoblasts/drug effects; Osteoblasts/metabolism; Osteocytes/drug effects; Osteocytes/metabolism; Proteins/metabolism; Proteins/pharmacology; RNA, Messenger/metabolism; Rats; Recombinant Fusion Proteins/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction/physiology; Transforming Growth Factor beta/metabolism; Transforming Growth Factor beta/pharmacology; Transforming Growth Factor beta1; Wnt Proteins/antagonists & inhibitors; Wnt Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SFRP1

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0001649: osteoblast differentiation

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0071773: cellular response to BMP stimulus

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0071560: cellular response to transforming growth factor beta stimulus

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0071380: cellular response to prostaglandin E stimulus

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0071347: cellular response to interleukin-1

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0071305: cellular response to vitamin D

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SFRP1

involved_in

GO:0043065: positive regulation of apoptotic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:SFRP1

involved_in

GO:0030178: negative regulation of Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:SFRP1

involved_in

GO:0071380: cellular response to prostaglandin E stimulus

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:SFRP1

involved_in

GO:0001649: osteoblast differentiation

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:SFRP1

involved_in

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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