Identification of the homeobox protein Prx1 (MHox, Prrx-1) as a regulator of osterix expression and mediator of tumor necrosis factor α action in osteoblast differentiation

Lu, Xian; Beck, George R.; Gilbert, Linda; Camalier, Corinne E.; Bateman, Nicholas W.; Hood, Brian L.; Conrads, Thomas P.; Kern, Michael J.; You, Sylvaine; Chen, Hong; Nanes, Mark S.

doi:10.1002/jbmr.203

Cited by 54 publications

(43 citation statements)

References 61 publications

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“…7B). Importantly, short-term administration of TNF-a caused a transcriptional repression of Sp7, but not of Runx2, thereby providing a potential molecular explanation for the negative influence of TNF-a on osteogenic differentiation, in agreement with previous studies (27,28). We next addressed the question of whether CD11b 2 bone marrow cells from Cpdm mice would display intact transcriptional activation of the TNF-a target genes Il6, Tnfaip3, and Nfkbia at day 5 of osteogenic differentiation.…”

Section: Primary Calvarial Cells From Cpdm Mice Display Impaired Ostesupporting

confidence: 79%

Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells

Jeschke

Catalá-Lehnen

Sieber

et al. 2015

The Journal of Immunology

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The cytosolic protein Sharpin is a component of the linear ubiquitin chain assembly complex, which regulates NF-κB signaling in response to specific ligands, such as TNF-α. Its inactivating mutation in chronic proliferative dermatitis mutation (Cpdm) mice causes multiorgan inflammation, yet this phenotype is not transferable into wild-type mice by hematopoietic stem cell transfer. Recent evidence demonstrated that Cpdm mice additionally display low bone mass, and that this osteopenia is corrected by Tnf deletion. Because the cellular mechanism underlying this pathology, however, was still undefined, we performed a thorough skeletal phenotyping of Cpdm mice on the basis of nondecalcified histology and cellular and dynamic histomorphometry. We show that the trabecular and cortical osteopenia in Cpdm mice is solely explained by impaired bone formation, whereas osteoclastogenesis is unaffected. Consistently, Cpdm primary calvarial cells display reduced osteogenic capacity ex vivo, and the same was observed with CD11b− bone marrow cells. Unexpectedly, short-term treatment of these cultures with TNF-α did not reveal an impaired molecular response in the absence of Sharpin. Instead, genome-wide and gene-specific expression analyses revealed that Cpdm mesenchymal cells display increased responsiveness toward TNF-α–induced expression of specific cytokines, such as CXCL5, IL-1β, and IL-6. Therefore, our data not only demonstrate that the skeletal defects of Cpdm mice are specifically caused by impaired differentiation of osteoprogenitor cells, they also suggest that increased cytokine expression in mesenchymal bone marrow cells contributes to the inflammatory phenotype of Cpdm mice.

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Section: Primary Calvarial Cells From Cpdm Mice Display Impaired Ostesupporting

confidence: 79%

Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells

Jeschke

Catalá-Lehnen

Sieber

et al. 2015

The Journal of Immunology

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“…However, TNFα also blocks BMP2 signaling pathway and overrides its protective effect on Runx2 by up-regulating Smad7 and/or promoting proteolysis of Smads [87][88][89]. In addition, TNFα down-regulates both the expression and activity of another osteogenic key factor, Osterix (Osx) through the MEK1/ERK1 signaling cascade [90,91]. Increasing numbers of evidence link microRNAs (miRNAs) to TNFα-regulated bone metabolism.…”

Section: Inflammatory Cytokinesmentioning

confidence: 99%

The Role of Bone Marrow Microenvironment in Governing the Balance between Osteoblastogenesis and Adipogenesis

Liu

Zuo

et al. 2016

Aging and disease

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ABSTRACT:In the adult bone marrow, osteoblasts and adipocytes share a common precursor called mesenchymal stem cells (MSCs). The plasticity between the two lineages has been confirmed over the past decades, and has important implications in the etiology of bone diseases such as osteoporosis, which involves an imbalance between osteoblasts and adipocytes. The commitment and differentiation of bone marrow (BM) MSCs is tightly controlled by the local environment that maintains a balance between osteoblast lineage and adipocyte. However, pathological conditions linked to osteoporosis can change the BM microenvironment and shift the MSC fate to favor adipocytes over osteoblasts, and consequently decrease bone mass with marrow fat accumulation. This review discusses the changes that occur in the BM microenvironment under pathological conditions, and how these changes affect MSC fate. We suggest that manipulating local environments could have therapeutic implications to avoid bone loss in diseases like osteoporosis.

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“…shown to be present on MC3T3 cells and primary mesenchymal stromal cells before [247] which is consistent with my qRT-PCR results. These findings demonstrate that all the progenitor cell populations isolated from the naïve muscle can potentially differentiate towards one of the mesodermal lineage -osteogenic, and these differentiation capabilities can be further amplified by culture in lineage-specific induction conditions as they do express Osteocalcin, Runx2, collagen type 1a and Prrx1…”

Section: Discussionsupporting

confidence: 89%

Understanding heterotopic ossification after spinal cord injury

Kulina¹

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Neurological heterotopic ossification (NHO) is a frequent complication of spinal cord and traumatic brain injuries (15-25% of patients) and manifests as abnormal ossification of soft tissues near joints. NHO is very debilitating and further delays rehabilitation as it causes pain, joint deformation and ankylosis and vascular and nerve compression. In the absence of an animal model the mechanisms leading to NHO are unknown and consequently there is no preventive treatment. The only effective approach to eliminate HO is complicated and expensive surgical resection. However these surgeries are delicate and can be challenging as they are performed once the NHO are mature, often large and incapacitating entrapping large blood vessels and nerves.To elucidate NHO pathophysiology, we have developed the first animal model of NHO in genetically unmodified mice. Mice underwent a spinal cord transection (SCI); muscular inflammation was induced by intramuscular injection of cardiotoxin in limbs (IM-CTX).Formation of NHO was followed by μCT and immunohistology.SCI alone or muscular inflammation alone did not induce NHO in mice. The combination of both SCI and muscular inflammation was necessary to induce NHO. This is consistent with clinical observations as NHO incidence is higher in patients with severe trauma or concomitant infection. Abundant F4/80 + macrophages, which can provide pro-anabolic support in bone formation, were detected within the inflamed muscle and associated with areas of intramuscular bone formation (confirmed by von Kossa and collagen type 1 staining). In vivo depletion of phagocytic macrophages with clodronate-loaded liposomes prevented NHO formation whereas Zoledronate treatment exacerbated NHO. This supports our hypothesis that macrophage-mediated inflammation is a key activator of NHO following SCI. To further identify the source and type of macrophages, involved in the bone formation after SCI and test some potential treatment options different knock-out mouse models were investigated. My data suggest that local muscle residential macrophages potentially play an important role in NHO.In addition we identified several populations of muscle progenitor cells that are prone to osteogenic differentiation in vitro. These data suggest that the mesenchymal progenitors that differentiate into osteoblasts in HO following spinal cord injury are already present in healthy muscles and therefore can be derived from local muscle progenitor cells rather than being recruited from the remote site, such as bone marrow.iii Finally we investigated why SCI was necessary for NHO development. My hypothesis was that SCI causes release of systemic factors priming NHO. In support of this, I showed that NHO developed in non-paralysed inflamed front limbs of mice with SCI. Also, blood plasma from mice with SCI and IM-CTX induced osteogenic differentiation of cultured muscle mesenchymal progenitor cells (mMPC) sorted from naïve mice. This suggests that systemic factors facilitating NHO, such as substance P and G-CSF are ...

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Identification of the homeobox protein Prx1 (MHox, Prrx-1) as a regulator of osterix expression and mediator of tumor necrosis factor α action in osteoblast differentiation

Cited by 54 publications

References 61 publications

Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells

Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells

The Role of Bone Marrow Microenvironment in Governing the Balance between Osteoblastogenesis and Adipogenesis

Understanding heterotopic ossification after spinal cord injury

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