Wnt Signaling Inhibits Osteoclast Differentiation by Activating Canonical and Noncanonical cAMP/PKA Pathways

Megan Weivoda, Ming Ruan, Christine M. Hachfeld, Larry Pederson, Alan Howe, Rachel A. Davey, Jeffrey D. Zajac, Yasuhiro Kobayashi, Bart O. Williams, Jennifer J Westendorf, Sundeep Khosla, Merry Jo Oursler

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Although there has been extensive characterization of the Wnt signaling pathway in the osteoblast lineage, the effects of Wnt proteins on the osteoclast lineage are less well studied. We found that osteoclast lineage cells express canonical Wnt receptors. Wnt3a reduced osteoclast formation when applied to early bone-marrow macrophage (BMM) osteoclast differentiation cultures, whereas late addition did not suppress osteoclast formation. Early Wnt3a treatment inactivated the crucial transcription factor NFATc1 in osteoclast progenitors. Wnt3a led to the accumulation of nuclear β-catenin, confirming activation of canonical Wnt signaling. Reducing low-density lipoprotein receptor-related proteins (Lrp) 5 and Lrp6 protein expression prevented Wnt3a-induced inactivation of NFATc1; however, deletion of β-catenin did not block Wnt3a inactivation of NFATc1, suggesting that this effect was mediated by a noncanonical pathway. Wnt3a rapidly activated the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and pharmacological stimulation of cAMP/PKA signaling suppressed osteoclast differentiation; Wnt3a-induced NFATc1 phosphorylation was blocked by inhibiting interactions between PKA and A-kinase anchoring proteins (AKAPs). These data indicate that Wnt3a directly suppresses osteoclast differentiation through both canonical (β-catenin) and noncanonical (cAMP/PKA) pathways in osteoclast precursors. In vivo reduction of Lrp5 and Lrp6 expressions in the early osteoclast lineage via Rank promoter Cre recombination reduced trabecular bone mass, whereas disruption of Lrp5/6 expression in late osteoclast precursors via cathepsin K (Ctsk) promoter Cre recombination did not alter the skeletal phenotype. Surprisingly, reduction of Lrp5/6 in the early osteoclast lineage decreased osteoclast numbers, as well as osteoblast numbers. Published studies have previously noted that β-catenin signaling is required for osteoclast progenitor proliferation. Our in vivo data suggest that Rank promoter Cre-mediated deletion of Lrp5/6 may similarly impair osteoclast progenitor proliferation.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - 2015

Fingerprint

Osteoclasts
Cyclic AMP-Dependent Protein Kinases
Cyclic AMP
Catenins
Osteoblasts
Genetic Recombination
Low Density Lipoprotein Receptor-Related Protein-5
Wnt Receptors
Wnt Proteins
Wnt Signaling Pathway
Protein Kinases

Keywords

  • Osteoclast differentiation
  • PKA
  • WNT
  • β-catenin

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Wnt Signaling Inhibits Osteoclast Differentiation by Activating Canonical and Noncanonical cAMP/PKA Pathways. / Weivoda, Megan; Ruan, Ming; Hachfeld, Christine M.; Pederson, Larry; Howe, Alan; Davey, Rachel A.; Zajac, Jeffrey D.; Kobayashi, Yasuhiro; Williams, Bart O.; Westendorf, Jennifer J; Khosla, Sundeep; Oursler, Merry Jo.

In: Journal of Bone and Mineral Research, 2015.

Research output: Contribution to journalArticle

Weivoda, Megan ; Ruan, Ming ; Hachfeld, Christine M. ; Pederson, Larry ; Howe, Alan ; Davey, Rachel A. ; Zajac, Jeffrey D. ; Kobayashi, Yasuhiro ; Williams, Bart O. ; Westendorf, Jennifer J ; Khosla, Sundeep ; Oursler, Merry Jo. / Wnt Signaling Inhibits Osteoclast Differentiation by Activating Canonical and Noncanonical cAMP/PKA Pathways. In: Journal of Bone and Mineral Research. 2015.
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AU - Howe, Alan

AU - Davey, Rachel A.

AU - Zajac, Jeffrey D.

AU - Kobayashi, Yasuhiro

AU - Williams, Bart O.

AU - Westendorf, Jennifer J

AU - Khosla, Sundeep

AU - Oursler, Merry Jo

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