Sp proteins and Runx2 mediate regulation of matrix gla protein (MGP) expression by parathyroid hormone

Abstract

As part of its catabolic action in bone, parathyroid hormone (PTH) inhibits extracellular matrix mineralization. We previously showed that PTH dose-dependently induces matrix gla protein (MGP) expression in osteoblasts and this induction is at least partially responsible for PTHmediated inhibition of mineralization. Recently, we identified PKA and ERK/MAPK as the key signaling pathways involved in PTH regulation of MGP expression. The goal of this study was to further characterize the mechanism by which PTH stimulates expression of MGP. Deletion analysis of the murine Mgp gene promoter identified a PTH-responsive region between -173 bp and -49 bp. Using gel-mobility shift assays we found that Sp1, Sp3 and Runx2 bind to distinct sites within this region. Mutation of either the Sp or the Runx2 site reduced MGP induction by PTH, while mutation of both sites completely abolished PTH responsiveness. Overexpression of Runx2 or Sp1 activated the Mgp reporter, while Sp3 was a dose-dependent repressor of MGP expression. Collectively, these data show that PTH regulates MGP gene transcription in osteoblasts through altered activities of Sp and Runx2 transcription factors.

Dual transcriptional regulation by runx2 of matrix Gla protein in Xenopus laevis

“…This is the first demonstration of a negative runx2 regulation in Xenopus MGP, but is consistent with observations of Runx2 function in other organisms (Levanon et al, 1998;Drissi et al, 2000;Javed et al, 2000;McLarren et al, 2000;Chen et al, 2005). This work provides a direct demonstration that runx2 regulates the expression of MGP, as reflected by changes in transcription, in agreement with recently published data (Suttamanatwong et al, 2009). In fact, during the preparation of this manuscript, Suttamanatwong et al (2009) described that the Fig.…”

“…Despite this large array of possible regulatory elements, only a few have been confirmed to mediate transcriptional regulation of MGP. These include (i) a negative responsive element identified in human MGP and shown to function as common binding site for both the RA receptor complex and the CAAT binding protein (Kirfel et al, 1997), and conserved in the distal promoter of MGP in the marine fish Sparus aurata (Conceição et al, 2008); (ii) a polymorphism within the human MGP promoter shown to affect binding of the AP-1 complex, resulting in altered transcription (Farzaneh-Far et al, 2001); (iii) a partially-defined sequence in the 5′-flanking region of mouse MGP gene identified as sufficient for transcriptional activation by FGF2 (Stheneur et al, 2003); and (iv) Sp proteins and Runx2 mediating MGP transcription upon parathyroid hormone (PTH) treatment (Suttamanatwong et al, 2009). …”

A TNF Variant that Associates with Susceptibility to Musculoskeletal Disease Modulates Thyroid Hormone Receptor Binding to Control Promoter Activation

“…Our data indicates that TR-α may modulate a bone loss phenotype through enhanced TNF induction independent of TH. In contrast, Sp1 binding sites are occupied by a family of ubiquitously expressed transcription factors, that control of expression for “house-keeping” genes and hormones and is thought to play a role in the regulation of early development and metabolism [29], in-keeping with our observation that the ‘G’ allele at the rs361525 locus is relatively non-inducible. Our findings suggest a functionally relevant novel mechanism for modulating transcriptional activation of the TNF promoter (Figure 6B), and that TR may modulate responses to agonists signaling through TLR-2, TLR-4, and the inflammasome, which are important inducible pathways in inflammatory arthritis and periprosthetic osteolysis [30].…”

Plasma Desphospho-Uncarboxylated Matrix Gla Protein as a Marker of Kidney Damage and Cardiovascular Risk in Advanced Stage of Chronic Kidney Disease

“…Westenfeld et al did not find a relationship between dp-ucMGP and mineral disturbances in the HD population [16], but in these patients there are additional factors which may influence PTH levels than in non-dialyzed CKD patients. In experimental studies it was shown that PTH induced MGP expression, and it was postulated that this induction may be critical for the inhibition of osteoblast mineralization [26,27]. Our observations may be relevant for this explanation because secondary hyperparathyroidism is one of the non-traditional risk factors of CV complications in CKD [28].…”