NFAT Signaling in Osteoblasts Regulates the Hematopoietic Niche in the Bone Microenvironment

Abstract

Osteoblasts support hematopoietic cell development, including B lymphopoiesis. We have previously shown that the nuclear factor of activated T cells (NFAT) negatively regulates osteoblast differentiation and bone formation. Interestingly, in smooth muscle, NFAT has been shown to regulate the expression of vascular cellular adhesion molecule-1 (VCAM-1), a mediator of cell adhesion and signaling during leukocyte development. To examine whether NFAT signaling in osteoblasts regulates hematopoietic development in vivo, we generated a mouse model expressing dominant-negative NFAT driven by the 2.3 kb fragment of the collagen-αI promoter to disrupt NFAT activity in osteoblasts (dnNFATOB). Bone histomorphometry showed that dnNFATOB mice have significant increases in bone volume (44%) and mineral apposition rate (131%) and decreased trabecular thickness (18%). In the bone microenvironment, dnNFATOB mice displayed a significant increase (87%) in Lineage−cKit+Sca-1+ (LSK) cells and significant decreases in B220+CD19−IgM− pre-pro-B cells (41%) and B220+CD19+IgM+ immature B cells (40%). Concurrent with these findings, LSK cell differentiation into B220+ cells was inhibited when cocultured on differentiated primary osteoblasts harvested from dnNFATOB mice. Gene expression and protein levels of VCAM-1 in osteoblasts decreased in dnNFATOB mice compared to controls. These data suggest that osteoblast-specific NFAT activity mediates early B lymphopoiesis, possibly by regulating VCAM-1 expression on osteoblasts.

Activation Of Nfatc2 in osteoblasts causes osteopenia

“…The increased number of osteoblasts in the context of Nfatc2 activation in male mice is consistent with the increased osteoblast number and disorganized bone formation reported in mice overexpressing a constitutively active form of Nfatc1 in osteoblasts, although in this model an increase in bone volume was reported (Winslow et al, 2006). More importantly, expression of a dominant negative form of Nfatc1 in cells of the osteoblastic lineage increased bone volume, findings that are consistent with a suppressive effect of Nfat in osteoblastic function (Sesler and Zayzafoon, 2013). Collectively, these observations suggest that Nfatc1 and Nfatc2 act through similar mechanisms to suppress osteoblast function and bone formation.…”

DC-STAMP: A Key Regulator in Osteoclast Differentiation

“…IL‐17A induces cathepsin K and MMP‐9 expression in osteoclasts via celecoxib‐blocked prostaglandin E2 in osteoblasts (Zhang et al, ). NFATc1 is a transcription factor that regulates many biological pathways including OB and OC differentiation (Stern, ; Winslow et al, ; Choo et al, ; Penolazzi et al, ; Sesler and Zayzafoon, ). In addition, Pin‐1 is the other factor that regulates not only DC‐STAMP for OC development, but also Runx2 for OB differentiation (Islam et al, ).…”

RCANs regulate the convergent roles of NFATc1 in bone homeostasis

“…Calcineurin-NFATc1 signaling is essential and sufficient for osteoclast differentiation, while the roles of calcineruin-NFATc1 signaling in osteoblasts are still controversial7891011121518. To verify the roles of calcineurin-NFATc1 signaling in osteoblasts, previous studies used calcineurin inhibitors in vitro or murine animal models, where calcineurin-NFATc1 signaling may be regulated by multiple factors10.…”

“…Nuclear factor of activated T cells c1 (NFATc1) may be profoundly involved in the regulation of bone homeostasis as it controls both osteoclast and osteoblast differentiation78910111213. When NFATc1 is dephosphorylated by the cytoplasmic calcium/calmodulin/calcineurin complex, NFATc1 is activated and translocates to the nucleus where it regulates its target genes transcription in cooperation with other transcription factors1415.…”