Canonical Wnts function as potent regulators of osteogenesis by human mesenchymal stem cells

Liu, Guizhong; Vijayakumar, Sapna; Grumolato, Luca; Arroyave, Randy; Qiao, HuiFang; Akiri, Gal; Aaronson, Stuart A.

doi:10.1084/jem2064oia7

Cited by 4 publications

(5 citation statements)

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“…In a recent study, Rajalin et al (12) also proposed a positive role for ERRα in osteoblastic differentiation of MSCs using ERRα-knockout (KO) mice. Auld et al (13) showed similar results regarding the role of ERRα in mineralization of human MSCs and they found that native ERRα represses Wnt signaling, which has been shown to suppress osteogenesis in the human MSC system (29). Our results also showed that lentiviral-mediated ERRα knockdown reduced the osteogenic differentiation of PDLSCs that are tissue-specific MSCs.…”

Section: Discussionsupporting

confidence: 82%

Estrogen-related receptor α is involved in the osteogenic differentiation of mesenchymal stem cells isolated from human periodontal ligaments

Cai

Gao

Huang

et al. 2013

International Journal of Molecular Medicine

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Recently, it has been reported that the orphan nuclear receptor estrogen-related receptor α (ERRα) is involved in the osteogenic differentiation of mesenchymal stem cells (MSCs). Moreover, ERRα has been identified as a novel therapeutic target for treating osteoporosis and other bone diseases. Human periodontal ligament tissue-derived mesenchymal stem cells (hPDLSCs) have recently been used in stem cell-mediated therapies because of their multipotency, particularly toward osteogenic differentiation. However, it is still unclear whether ERRα can regulate the osteogenic differentiation of hPDLSCs. In the present study, we investigated the role of ERRα in the osteogenic differentiation of hPDLSCs in vitro. We isolated hPDLSCs and confirmed their capacity for multipotent differentiation. Furthermore, we examined ERRα expression in hPDLSCs by RT-PCR and immunocytochemistry. We found that the expression of ERRα mRNA was significantly increased during the late stage of osteogenic differentiation of hPDLSCs. Moreover, transfection of recombinant lentiviral-mediated miRNA targeting ERRα significantly suppressed ALP activity, mineralization capacity, and the mRNA expression of osteogenesis-related genes (ALP, OCN, RUNX2 and OPN) in hPDLSCs. Our results indicate that ERRα may promote the osteogenic differentiation of hPDLSCs in vitro.

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Section: Discussionsupporting

confidence: 82%

Estrogen-related receptor α is involved in the osteogenic differentiation of mesenchymal stem cells isolated from human periodontal ligaments

Cai

Gao

Huang

et al. 2013

International Journal of Molecular Medicine

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“…This finding suggests that this fibrous area may serve as a stromal compartment required to start differentiation of the cells adjacent to the bone spicules. Indeed, Liu et al recently reported that implanted bone marrow derived cells overexpressing Wnt1 develop a fibrous compartment and stimulate osteogenic differentiation of the Wnt1cells residing juxta-proximal of the CaP granules, therefore further supporting this hypothesis [63]. Alternatively, the fibrous tissue could be the result of a rapid proliferating fibroblast subpopulation either derived from the in vitro expanded HPDCs either infiltrated from the host environment.…”

Section: Discussionmentioning

confidence: 89%

A clinically relevant model of osteoinduction: a process requiring calcium phosphate and BMP/Wnt signalling

Eyckmans

Roberts

Schrooten

et al. 2010

J Cellular Molecular Medi

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In this study, we investigated a clinically relevant model of in vivo ectopic bone formation utilizing human periosteum derived cells (HPDCs) seeded in a Collagraft™ carrier and explored the mechanisms by which this process is driven. Bone formation occurred after eight weeks when a minimum of one million HPDCs was loaded on Collagraft™ carriers and implanted subcutaneously in NMRI nu/nu mice. De novo bone matrix, mainly secreted by the HPDCs, was found juxta-proximal of the calcium phosphate (CaP) granules suggesting that CaP may have triggered the ‘osteoinductive program’. Indeed, removal of the CaP granules by ethylenediaminetetraacetic acid decalcification prior to cell seeding and implantation resulted in loss of bone formation. In addition, inhibition of endogenous bone morphogenetic protein and Wnt signalling by overexpression of the secreted antagonists Noggin and Frzb, respectively, also abrogated osteoinduction. Proliferation of the engrafted HPDCs was strongly reduced in the decalcified scaffolds or when seeded with adenovirus-Noggin/Frzb transduced HPDCs indicating that cell division of the engrafted HPDCs is required for the direct bone formation cascade. These data suggest that this model of bone formation is similar to that observed during physiological intramembranous bone development and may be of importance when investigating tissue engineering strategies.

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“…In humans, heterozygous missense (gain-offunction) mutations in LRP5 result in van Buchem disease type 2 (endosteal hyperostosis) with elevated bone density, 26,27 and equivalent mutations in mice recapitulate the human high-bone-mass phenotype. 28 In mesenchymal stem cells, Wnt proteins play a role in sustaining stem cell self-renewal and differentiation potential, 29,30 and there is evidence that Wnt signaling in osteocytes is required for normal bone homeostasis. 31 The studies of mutations in LRP5, outlined above, place the canonical Wnt pathway in the early stages of bone development and suggest, in addition, that it has a role during osteoblast differentiation and proliferation.…”

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confidence: 99%

WNT1 Mutations in Families Affected by Moderately Severe and Progressive Recessive Osteogenesis Imperfecta

Pyott

Tran

Leistritz

et al. 2013

The American Journal of Human Genetics

195

158

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Osteogenesis imperfecta (OI) is a heritable disorder that ranges in severity from death in the perinatal period to an increased lifetime risk of fracture. Mutations in COL1A1 and COL1A2, which encode the chains of type I procollagen, result in dominant forms of OI, and mutations in several other genes result in recessive forms of OI. Here, we describe four recessive-OI-affected families in which we identified causative mutations in wingless-type MMTV integration site family 1 (WNT1). In family 1, we identified a homozygous missense mutation by exome sequencing. In family 2, we identified a homozygous nonsense mutation predicted to produce truncated WNT1. In family 3, we found a nonsense mutation and a single-nucleotide duplication on different alleles, and in family 4, we found a homozygous 14 bp deletion. The mutations in families 3 and 4 are predicted to result in nonsense-mediated mRNA decay and the absence of WNT1. WNT1 is a secreted signaling protein that binds the frizzled receptor (FZD) and the coreceptor low-density lipoprotein-receptor-related protein 5 (LRP5). Biallelic loss-of-function mutations in LRP5 result in recessive osteoporosis-pseudoglioma syndrome with low bone mass, whereas heterozygous gain-of-function mutations result in van Buchem disease with elevated bone density. Biallelic loss-of-function mutations in WNT1 result in a recessive clinical picture that includes bone fragility with a moderately severe and progressive presentation that is not easily distinguished from dominant OI type III.

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Canonical Wnts function as potent regulators of osteogenesis by human mesenchymal stem cells

Cited by 4 publications

References 1 publication

Estrogen-related receptor α is involved in the osteogenic differentiation of mesenchymal stem cells isolated from human periodontal ligaments

Estrogen-related receptor α is involved in the osteogenic differentiation of mesenchymal stem cells isolated from human periodontal ligaments

A clinically relevant model of osteoinduction: a process requiring calcium phosphate and BMP/Wnt signalling

WNT1 Mutations in Families Affected by Moderately Severe and Progressive Recessive Osteogenesis Imperfecta

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