Homeobox Protein Msx2 Acts as a Molecular Defense Mechanism for Preventing Ossification in Ligament Fibroblasts

Yoshizawa, Tatsuya; Takizawa, Fumio; Iizawa, Futabako; Ishibashi, Osamu; Kawashima, Hiroyuki; Matsuda, Akio; Endo, Naoto

doi:10.1128/mcb.24.8.3460-3472.2004

Cited by 105 publications

(96 citation statements)

References 50 publications

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“…The molecular mechanism by which the PDL is maintained and not ossified has not yet been fully clarified. Msx2, which is a transcriptional factor with a homeobox domain, has recently been reported to be dominantly expressed in the PDL and to suppress PDL cytodifferentiation and mineralization through the inhibition of Runx2 functions (35). Another study revealed that S100A4, which is an intracellular calcium-binding protein, suppresses differentiation of PDL cells as well as osteoblasts (36,37).…”

Section: Discussionmentioning

confidence: 99%

PLAP-1/Asporin, a Novel Negative Regulator of Periodontal Ligament Mineralization

Yamada¹,

Tomoeda²,

Ozawa³

et al. 2007

Journal of Biological Chemistry

182

189

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Periodontal ligament-associated protein-1 (PLAP-1)/asporin is a recently identified novel member of the small leucine-rich repeat proteoglycan family. PLAP-1/asporin is involved in chondrogenesis, and its involvement in the pathogenesis of osteoarthritis has been suggested. We report that PLAP-1/asporin is also expressed specifically and predominantly in the periodontal ligament (PDL) and that it negatively regulates the mineralization of PDL cells. In situ hybridization analysis revealed that PLAP-1/asporin was expressed specifically not only in the PDL of an erupted tooth but also in the dental follicle, which is the progenitor tissue of the PDL during tooth development. Overexpression of PLAP-1/asporin in mouse PDL-derived clone cells interfered with both naturally and bone morphogenetic protein 2 (BMP-2)-induced mineralization of the PDL cells. On the other hand, knockdown of PLAP-1/asporin transcript levels by RNA interference enhanced BMP-2-induced differentiation of PDL cells. Furthermore co-immunoprecipitation assays showed a direct interaction between PLAP-1/asporin and BMP-2 in vitro, and immunohistochemistry staining revealed the co-localization of PLAP-1/asporin and BMP-2 at the cellular level. These results suggest that PLAP-1/ asporin plays a specific role(s) in the periodontal ligament as a negative regulator of cytodifferentiation and mineralization probably by regulating BMP-2 activity to prevent the periodontal ligament from developing non-physiological mineralization such as ankylosis.

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Section: Discussionmentioning

confidence: 99%

PLAP-1/Asporin, a Novel Negative Regulator of Periodontal Ligament Mineralization

Yamada¹,

Tomoeda²,

Ozawa³

et al. 2007

Journal of Biological Chemistry

182

189

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“…In addition to the transcriptional repression of bone marker genes, Msx2 also inhibits the function of key osteogenic regulators, such as Runx2, Dlx3, and Dlx5, through the DNA binding-independent protein-protein interactions and/or the binding competition on the same DNA sequences (9,11,14). Moreover, Msx2 expression is higher in periodontal ligament and tendon cells than in osteoblastic cells (16), which suggests that Msx2 functions in a molecular defense capacity to prevent the ossification of the periodontal space. These results implicate Msx2 in the negative regulation of osteogenesis.…”

mentioning

confidence: 99%

The Boston-type Craniosynostosis Mutation MSX2 (P148H) Results in Enhanced Susceptibility of MSX2 to Ubiquitin-dependent Degradation

Yoon

Cho

et al. 2008

Journal of Biological Chemistry

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Boston-type craniosynostosis is caused by a single amino acid substitution, P148H, in the transcription factor MSX2. The increased binding affinity of MSX2 (P148H) to the response element has led many to hypothesize that the substitution is a gainof-function mutation. However, there have been conflicting reports on the function of MSX2, and by extension, the nature of the P148H mutation remains unclear. In this study, we have examined the molecular mechanism of MSX2 function and the nature of the P148H mutation. During cranial suture closure of rodent, Msx2 expression was detected in the suture space. Overexpression of wild type MSX2 in mesenchymal cells stimulated cell proliferation and cyclin D1 expression, whereas P148H mutant did not. These results indicated that MSX2 is involved in maintaining the suture space by stimulating suture mesenchymal cell proliferation and that P148H is defective in this process. The protein levels of P148H were lower than wild type Msx2 (Msx2-WT), and pulse-chase experiments indicated that the mutant protein has a shorter half-life than the Msx2-WT protein. The ubiquitylation level of P148H was greater than that of Msx2-WT. The degradation of Msx2 was mediated by Praja1, and the P148H mutant was degraded more effectively than WT. The ubiquitylation of Msx2-WT was higher in the presence of Msx2 (P148H), which indicated that P148H functions as a dominant-negative mutant. Collectively, the primary function of MSX2 in suture closure is the induction of cell proliferation and suture maintenance, and the mutation results in an increased susceptibility of both wild type and mutant MSX2 to proteasomal degradation.

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“…Constitutively activated Smad1 overexpression was reported to induce myoblast osteogenic differentiation, whereas nuclear translocation of Smad4 inhibited myoblast myogenic differentiation [34]. It is not known whether Smad proteins and MSX2 also function to inhibit osteogenic differentiation and promote TDSC tenogenic differentiation, as reported in previous studies [30,32,34]; further study is required. Other factors, such as mechanical loading [35] and local extracellular matrix environment [9], may also function to suppress TDSC osteogenesis inside the tendon midsubstance.…”

Section: Discussionmentioning

confidence: 78%

“…A regulatory mechanism to prevent erroneous TDSCs differentiation to junctional cell types (bone, chondrocytes, muscles) in tendon midsubstances other than tenocytes therefore may be in place in order to maintain tendon homeostasis. In this regard, MSX2 was reported to act as a molecular defence mechanism for preventing ossification in ligament fibroblasts [32]. An activated form of Smad8 protein inhibited the osteogenic pathway in MSCs known to be induced by BMP-2 while promoting tenogenic differentiation [33].…”

Section: Discussionmentioning

confidence: 99%

Higher BMP receptor expression and BMP-2-induced osteogenic differentiation in tendon-derived stem cells compared with bone-marrow-derived mesenchymal stem cells

Rui

Lui

Lee

et al. 2011

International Orthopaedics (SICOT)

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Purpose Surgical reattachment of tendon to bone often fails due to regeneration failure of the specialised tendon-bone junction (TBJ). The use of mesenchymal stem cells for TBJ regeneration has been reported with promising results. Tendonderived stem cells (TDSCs) with high proliferative and multilineage differentiation potential have been isolated. As stem cells residing in tendons, TDSCs can be considered a new cell source for TBJ repair. Bone morphogenic protein 2 (BMP-2) is a potent osteogenic factor with roles in normal bone healing and pathological ectopic bone formation in soft tissues. The use of BMP-2 to promote TBJ repair has been well reported. This study aimed to compare TDSCs to the gold standard bonemarrow-derived mesenchymal stem cells (BMSCs) with respect to osteogenic response to BMP-2 in vitro. Method The clonogenicity and multi-differentiation potential of TDSCs and BMSCs were identified by colony-formingunit assay, osteogenic, adipogenic and chondrogenic differentiation assays. Their osteogenic response to BMP-2 in vitro was examined by alkaline phosphatase (ALP) cytochemical staining, ALP activity assay and Alizarin red S staining of calcium nodule formation. Messenger RNA (mRNA) and BMP receptor (types IA, IB and II) protein expression were examined by quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blotting. Results Our results showed that both TDSCs and BMSCs exhibited stem cell properties, including clonogenicity and multi-differentiation potential. TDSCs expressed higher mRNA and protein levels of BMP receptors IA, IB and II. They also exhibited higher osteogenic differentiation with and without BMP-2 stimulation compared with BMSCs. Conclusions TDSCs with/without BMP-2 might be an attractive source for TBJ repair compared with BMSCs.

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Homeobox Protein Msx2 Acts as a Molecular Defense Mechanism for Preventing Ossification in Ligament Fibroblasts

Cited by 105 publications

References 50 publications

PLAP-1/Asporin, a Novel Negative Regulator of Periodontal Ligament Mineralization

PLAP-1/Asporin, a Novel Negative Regulator of Periodontal Ligament Mineralization

The Boston-type Craniosynostosis Mutation MSX2 (P148H) Results in Enhanced Susceptibility of MSX2 to Ubiquitin-dependent Degradation

Higher BMP receptor expression and BMP-2-induced osteogenic differentiation in tendon-derived stem cells compared with bone-marrow-derived mesenchymal stem cells

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