The Secreted Protein Thrombospondin 2 Is an Autocrine Inhibitor of Marrow Stromal Cell Proliferation

Hankenson, Kurt D.; Börnstein, Paul

doi:10.1359/jbmr.2002.17.3.415

Cited by 64 publications

(66 citation statements)

References 56 publications

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“…Thus, detection of silver ions is an indirect measure of calcium content (44). Alizarin Red S is an anthraquinone derivative that complexes with calcium, resulting in an orange-red-colored product (45,46).…”

Section: Methodsmentioning

confidence: 99%

Wnt Signaling Stimulates Osteoblastogenesis of Mesenchymal Precursors by Suppressing CCAAT/Enhancer-binding Protein α and Peroxisome Proliferator-activated Receptor γ

Kang

Bennett

Gerin

et al. 2007

Journal of Biological Chemistry

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Section: Methodsmentioning

confidence: 99%

Wnt Signaling Stimulates Osteoblastogenesis of Mesenchymal Precursors by Suppressing CCAAT/Enhancer-binding Protein α and Peroxisome Proliferator-activated Receptor γ

Kang

Bennett

Gerin

et al. 2007

Journal of Biological Chemistry

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369

270

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“…Using anti-TSP1-and anti-TSP2-specific antibodies, we observed high levels of TSP1 ( Figure 4A) but no TSP2 ( Figure 4B) in wild-type platelets mildly activated with thrombin. The same anti-TSP2 antibody has been used successfully to detect TSP2 in bone marrow stroma cells (BMSCs), 28 skin fibroblasts, 16 and in MKs ( Figure 5A). We were also unable to detect TSP2 in platelet lysates by Western analysis (data not shown).…”

Section: Tsp2 Is Lacking In Plateletsmentioning

confidence: 99%

“…Previously we have shown that TSP2-null mice have increased numbers of BMSCs, 38 and recently we have determined that BMSCs are a major source of TSP2 in the bone marrow. 28 The influence of BMSCs on MKs has been demonstrated by coculture studies in which these cells were shown to induce MK growth and proplatelet formation by secreting TPO and stroma derived factor-1. [39][40][41] However, the paracrine effects of BMSCs on the maturation of MKs and proplatelet formation are rendered ineffective when BMSCs and MKs are in direct contact.…”

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confidence: 99%

Megakaryocytes require thrombospondin-2 for normal platelet formation and function

Kyriakides

Rojnuckarin

Reidy

et al. 2003

Blood

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Mice that lack the matricellular angiogenesis inhibitor, thrombospondin-2 (TSP2), display a bleeding diathesis, despite normal blood coagulation and the lack of thrombocytopenia. Although platelets do not contain detectable levels of TSP2, TSP2-null platelets are compromised in their ability to aggregate in vivo in response to denudation of the carotid artery endothelium, and in vitro following exposure to adenosine diphosphate (ADP) . IntroductionThrombospondin-2 (TSP2) is a potent inhibitor of angiogenesis that participates in the processes of development and tissue repair. 1 Specifically, TSP2 is expressed during embryonic development, and during healing of dermal wounds and the foreign body response to implanted biomaterials. [2][3][4][5] In addition, TSP2 has been implicated in the process of tumor growth where it has been shown to inhibit blood vessel formation and limit the growth of squamous cell carcinomas. 6 As a matricellular protein, TSP2 can interact with both cell-surface receptors and extracellular matrix (ECM) components and is believed to function as a modulator of cell-matrix interactions. 7 We have previously shown that mice that lack TSP2 develop a pleiotropic phenotype characterized by connective tissue abnormalities that include abnormal collagen fibrillogenesis. 8 In addition, these mice display increased angiogenesis, increased bone formation, reduced fibroblast adhesion, and an unexpected bleeding diathesis. We hypothesized that the latter could result from an intrinsic qualitative platelet defect, from a subendothelial defect, or both. While we have preliminary evidence for the contribution of a connective tissue abnormality to the bleeding diathesis ("Discussion"), we were surprised to find a reproducible defect in aggregation in the response of TSP2-null platelets to a mild agonist. Since TSP2, unlike TSP1, is not present in platelets we hypothesized that the abnormality might arise earlier, during megakaryocyte (MK) development.Proplatelets are long processes that issue from the surface of fully mature MKs, migrate through the endothelial barrier of marrow sinusoids, and fragment into platelets. At the molecular level, little is understood regarding the regulation of these events, except that ␤1 tubulin and protein kinase C␣ (PKC␣) are essential. 9,10 Analysis of platelet function on the other hand, has benefited from the generation of genetic disruptions in mice that lead to the development of platelet abnormalities. Such models have provided new insights into the functional significance of several platelet proteins. For example, deficiencies in -calpain, 11 ␣ IIb ␤ 3 , 12 platelet endothelial cell adhesion molecule-1 (PECAM-1), 13 and von Willebrand factor (VWF) 14 have led to the development of distinct platelet abnormalities and/or bleeding diatheses. Interestingly, platelet aggregation defects are not always associated with prolonged bleeding times, as was seen in -calpain-null mice. 11 The opposite condition, in which a bleeding diathesis can develop without a platelet defect, ...

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“…13,14 TSP2-null mice show an increase in endocortical bone formation and increase cortical thickness that is secondary to enhanced marrow mesenchymal progenitor cell number. 15,16 As well, TSP2-null mice heal excisional skin wounds at an accelerated rate and with less scarring than WT mice, in part due to increased angiogenesis. 17,18 In a simple bone regeneration model TSP2-null mice show enhanced callus vascularization and secondarily to this vascularity show enhanced intramembranous bone repair.…”

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confidence: 99%

“…The concomitant increased vascularization levels could reasonably be assumed to cause these changes, but mesenchymal progenitors from TSP2-null mice have an increase in proliferation, 15,16 and TSPs also regulate apopotosis. However, future studies are needed to delineate the pathways by which enhanced revascularization in TSP2-null mice drives accelerated healing in the ischemic fracture model.…”

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confidence: 99%

Disruption of thrombospondin‐2 accelerates ischemic fracture healing

Miedel

Dishowitz

Myers

et al. 2012

Journal Orthopaedic Research

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Thrombospondin-2 (TSP2) is a matricellular protein that is highly up-regulated during fracture healing. TSP2 negatively regulates vascularity, vascular reperfusion following ischemia, and cutaneous wound healing. As well, TSP2-null mice show increased endocortical bone formation due to an enhanced number of mesenchymal progenitor cells and show increased cortical thickness. Mice deficient in TSP2 (TSP2-null) show an alteration in fracture healing, that is unrelated to their cortical bone phenotype, which is characterized by enhanced vascularization with a shift towards an intramembranous healing phenotype; thus, we hypothesized that there would be enhanced ischemic fracture healing in the absence of TSP2. We investigated whether an absence of TSP2 would enhance ischemic fracture healing utilizing Laser doppler, mCT and histological analysis. Ischemic tibial fractures were created in wildtype (WT) and TSP2-null mice and harvested 10, 20, or 40 days post-fracture. TSP2-null mice show enhanced vascular perfusion following ischemic fracture. At day 10 post-fracture, TSP2-null mice have 115% greater bone volume than WT mice. This is associated with a 122% increase in vessel density, 20% increase in cell proliferation, and 15% decrease in apoptosis compared to WT. At day 20, TSP2-null mice have 34% more bone volume, 51% greater bone volume fraction, and 37% more bone tissue mineral density than WT. By 40 days after fracture the TSP2-null mice have a 24% increase in bone volume fraction, but other parameters show no significant differences. These findings indicate TSP2 is a negative regulator of ischemic fracture healing and that in the absence of TSP2 bone regeneration is enhanced. Keywords: thrombospondin-2; ischemia; bone fracture healing Blood supply during fracture healing is crucial for proper bone repair. Vasodilation following fracture promotes edema and inflammation at the site of injury, and contributes to the development of the fracture hematoma. Inflammatory cells that occupy the hematoma produce cytokines and growth factors that then drive neovascularization which is essential for the next phases of repair. Intact vessels are required for new vessel formation to occur during the normal healing process.1,2 However, with a fracture injury there is almost always some disruption of established blood vessels. Thus, fractures with severely disrupted vascularization (ischemia) present a complex medical challenge. Up to 46% of patients with impaired vascular flow have complications during fracture repair, leading to delayed healing or nonunion that necessitates multiple surgeries that typically include staged bone grafting or possibly even amputation. [3][4][5] An important, yet largely untapped, therapeutic strategy to improve ischemic bone regeneration is to enhance vascularization at the fracture site. This can be achieved by either activating angiogenic pathways or by blocking angiogenesis inhibitors. Blocking angiogenic inhibitors has received relatively little attention as a therapeutic target in f...

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The Secreted Protein Thrombospondin 2 Is an Autocrine Inhibitor of Marrow Stromal Cell Proliferation

Cited by 64 publications

References 56 publications

Wnt Signaling Stimulates Osteoblastogenesis of Mesenchymal Precursors by Suppressing CCAAT/Enhancer-binding Protein α and Peroxisome Proliferator-activated Receptor γ

Wnt Signaling Stimulates Osteoblastogenesis of Mesenchymal Precursors by Suppressing CCAAT/Enhancer-binding Protein α and Peroxisome Proliferator-activated Receptor γ

Megakaryocytes require thrombospondin-2 for normal platelet formation and function

Disruption of thrombospondin‐2 accelerates ischemic fracture healing

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