Regulation of human bone marrow stromal cell proliferation and differentiation capacity by glucocorticoid receptor and AP-1 crosstalk

Cárcamo-Orive, Iván; Gaztelumendi, Ainhoa; Delgado, Jesús; Tejados, Naiara; Dorronsoro, Akaitz; Fernández-Rueda, Jon; Pennington, Daniel J.; Trigueros, César

doi:10.1002/jbmr.120

Cited by 69 publications

(64 citation statements)

References 42 publications

(31 reference statements)

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“…This is another important finding because divergent effects of PDGFR have been reported in MSC osteogenic differentiation. Although PDGF was reported to have positive or negative effects on bone marrowderived mesenchymal progenitor cell differentiation in vitro (51,52), PDGFR signaling was shown to promote bone formation in vivo (53)(54)(55). Consistently, we found that inhibition of PDGFR and FGFR abrogated hMSC osteogenic differentiation induced by the mutant Cbl, which strongly supports a role for these receptors in hMSC osteogenic differentiation.…”

Section: Discussionsupporting

confidence: 83%

The Casitas B Lineage Lymphoma (Cbl) Mutant G306E Enhances Osteogenic Differentiation in Human Mesenchymal Stromal Cells in Part by Decreased Cbl-mediated Platelet-derived Growth Factor Receptor α and Fibroblast Growth Factor Receptor 2 Ubiquitination

Sévère

Miraoui

Marie

2011

Journal of Biological Chemistry

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Human bone marrow-derived mesenchymal stromal cells (hMSCs) have the capacity to differentiate into several cell types including osteoblasts and are therefore an important cell source for bone tissue regeneration. A crucial issue is to identify mechanisms that trigger hMSC osteoblast differentiation to promote osteogenic potential. Casitas B lineage lymphoma (Cbl) is an E3 ubiquitin ligase that ubiquitinates and targets several molecules for degradation. We hypothesized that attenuation of Cbl-mediated degradation of receptor tyrosine kinases (RTKs) may promote osteogenic differentiation in hMSCs. We show here that specific inhibition of Cbl interaction with RTKs using a Cbl mutant (G306E) promotes expression of osteoblast markers (Runx2, alkaline phosphatase, type 1 collagen, osteocalcin) and increases osteogenic differentiation in clonal bone marrow-derived hMSCs and primary hMSCs. Analysis of molecular mechanisms revealed that the Cbl mutant increased PDGF receptor ␣ and FGF receptor 2 but not EGF receptor expression in hMSCs, resulting in increased ERK1/2 and PI3K signaling. Pharmacological inhibition of FGFR or PDGFR abrogated in vitro osteogenesis induced by the Cbl mutant. The data reveal that specific inhibition of Cbl interaction with RTKs promotes the osteogenic differentiation program in hMSCs in part by decreased Cbl-mediated PDGFR␣ and FGFR2 ubiquitination, providing a novel mechanistic approach targeting Cbl to promote the osteogenic capacity of hMSCs.Human bone marrow-derived mesenchymal stromal cells (MSCs) 3 are adherent cells that can differentiate into multiple lineages including chondroblasts, osteoblasts, and adipocytes in a specific environment (1-3). Adult human MSCs (hMSCs) are an important cell source for tissue repair and therapy in regenerative medicine (4, 5). One important limitation to using hMSCs is their limited potential to differentiate into functional bone-forming cells. An important challenge is therefore to develop strategies that can promote the ex vivo osteogenic potential of hMSCs for bone tissue regeneration (6, 7). This requires a better understanding of the signaling molecules that trigger MSC osteogenic differentiation.The osteogenic differentiation of MSCs is characterized by the expression of timely expressed genes such as Runx2, alkaline phosphatase (ALP), and type I collagen (Col1A1) followed by extracellular matrix mineralization (8, 9). The osteogenic potential of hMSCs can be promoted by proteins such as bone morphogenetic proteins that increase Runx2 expression and downstream osteoblast marker genes (10). Very recent studies indicate that activation of receptor tyrosine kinases (RTKs) such as platelet-derived growth factor (PDGFR) (11) or fibroblast growth factor receptor 2 (FGFR2) (12) promotes the osteogenic differentiation of human or murine MSCs. This effect results in part from activation of signaling pathways such as extracellular signal-regulated protein kinase (ERK1/2) and phosphatidylinositol kinase (PI3K), leading to activation of osteoblast marker ...

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Section: Discussionsupporting

confidence: 83%

The Casitas B Lineage Lymphoma (Cbl) Mutant G306E Enhances Osteogenic Differentiation in Human Mesenchymal Stromal Cells in Part by Decreased Cbl-mediated Platelet-derived Growth Factor Receptor α and Fibroblast Growth Factor Receptor 2 Ubiquitination

Sévère

Miraoui

Marie

2011

Journal of Biological Chemistry

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“…Multiple studies suggest that when ASC fate is committed to the adipogenic pathway, osteogenesis is concomitantly down regulated, consistent with observations in BMSCs [25,32]. This balance is suggested to be partly modulated by the presence and amount of glucocorticoid, the glucocorticoid receptor pathway activity, crosstalk with the Jak/STAT3 pathway, and the subsequent activation of the AP-1 pathway [33,34]. Other studies have suggested that an inverse relationship exists between donor age and ASC osteogenesis [35], and that ASCs from male donors exhibit increased osteogenic potential compared to ASCs from female donors in vitro [36].…”

Section: Discussionsupporting

confidence: 71%

Body mass index affects proliferation and osteogenic differentiation of human subcutaneous adipose tissue-derived stem cells

et al. 2013

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BackgroundObesity is associated with a higher risk of developing cancer and co-morbidities that are part of the metabolic syndrome. Adipose tissue is recognized as an endocrine organ, as it affects a number of physiological functions, and contains adipose tissue-derived stem cells (ASCs). ASCs can differentiate into cells of multiple lineages, and as such are applicable to tissue engineering and regenerative medicine. Yet the question of whether ASC functionality is affected by the donor’s body mass index (BMI) still exists.ResultsASCs were isolated from patients having different BMIs (BMI-ASCs), within the ranges of 18.5-32.8. It was hypothesized that overweight BMI-ASCs would be more compromised in early adipogenic and osteogenic potential, and ability to form colonies in vitro. BMI was inversely correlated with ASC proliferation and colony forming potential as assessed by CyQUANT proliferation assay (fluorescence- based measurement of cellular DNA content), and colony forming assays. BMI was positively correlated with early time point (day 7) but not later time point (day 15) intracytoplasmic lipid accumulation as assessed by Oil-Red-O staining. Alizarin red staining and RT-PCR for alkaline phosphatase demonstrated that elevated BMI resulted in compromised ASC mineralization of extracellular matrix and decreased alkaline phosphatase mRNA expression.ConclusionsThese data demonstrate that elevated BMI resulted in reduced ASC proliferation, and potentially compromised osteogenic capacity in vitro; thus BMI is an important criterion to consider in selecting ASC donors for clinical applications.

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“…In the current study, JNK signaling stimulated Runx2 activity, which had been reported to promote osteogenic differentiation of BMSCs (Cárcamo-Orive et al 2010;Huang et al 2012). Activation of the Wnt5a/Ror2 pathway by interleukin (IL)-1β had been reported to promote mesenchymal stem cell differentiation into osteoblasts (Sonomoto et al 2012).…”

Section: Discussionmentioning

confidence: 85%

Wnt5a/Ror2 Mediates Temporomandibular Joint Subchondral Bone Remodeling

et al. 2015

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Increased subchondral trabecular bone turnover due to imbalanced bone-resorbing and bone-forming activities is a hallmark of osteoarthritis (OA). Wnt5a/Ror2 signaling, which can derive from bone marrow stromal cells (BMSCs), takes a role in modulating osteoblast and osteoclast formation. We showed previously that experimentally unilateral anterior crossbites (UACs) elicited OA-like lesions in mice temporomandibular joints (TMJs), displaying as subchondral trabecular bone loss. Herein, we tested the role of BMSC-derived Wnt5a/Ror2 signaling in regulating osteoclast precursor migration and differentiation in this process. The data confirmed the decreased bone mass, increased tartrate-resistant acid phosphatase (TRAP)-positive cell number, and enhanced osteoclast activity in TMJ subchondral trabecular bone of UAC-treated rats. Interestingly, the osteoblast activity in the tissue of TMJ subchondral trabecular bone of these UAC-treated rats was also enhanced, displaying as upregulated expressions of osteoblast markers and increased proliferation, migration, and differentiation capabilities of the locally isolated BMSCs. These BMSCs showed an increased CXCL12 protein expression level and upregulated messenger RNA expressions of Rankl, Wnt5a, and Ror2. Ex vivo data showed that their capacities of inducing migration and differentiation of osteoclast precursors were enhanced, and these enhanced capabilities were restrained after blocking their Ror2 signaling using small interfering RNA (siRNA) assays. Reducing Ror2 expression in the BMSC cell line by siRNA or blocking the downstream signalings with specific inhibitors also demonstrated a suppression of the capacity of the BMSC cell line to promote Wnt5a-dependent migration (including SP600125 and cyclosporine A) and differentiation (cyclosporine A only) of osteoclast precursors. These findings support the idea that Wnt5a/Ror2 signaling in TMJ subchondral BMSCs enhanced by UAC promoted BMSCs to increase Cxcl12 and Rankl expression, in which JNK and/or Ca(2+)/NFAT pathways were involved and therefore were engaged in enhancing the migration and differentiation of osteoclast precursors, leading to increased osteoclast activity and an overall TMJ subchondral trabecular bone loss in the UAC-treated rats.

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Regulation of human bone marrow stromal cell proliferation and differentiation capacity by glucocorticoid receptor and AP-1 crosstalk

Cited by 69 publications

References 42 publications

The Casitas B Lineage Lymphoma (Cbl) Mutant G306E Enhances Osteogenic Differentiation in Human Mesenchymal Stromal Cells in Part by Decreased Cbl-mediated Platelet-derived Growth Factor Receptor α and Fibroblast Growth Factor Receptor 2 Ubiquitination

The Casitas B Lineage Lymphoma (Cbl) Mutant G306E Enhances Osteogenic Differentiation in Human Mesenchymal Stromal Cells in Part by Decreased Cbl-mediated Platelet-derived Growth Factor Receptor α and Fibroblast Growth Factor Receptor 2 Ubiquitination

Body mass index affects proliferation and osteogenic differentiation of human subcutaneous adipose tissue-derived stem cells

Wnt5a/Ror2 Mediates Temporomandibular Joint Subchondral Bone Remodeling

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