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PTH-enhanced structural allograft healing is associated with decreased angiopoietin-2-mediated arteriogenesis, mast cell accumulation, and fibrosis.

ABSTRACT: Recombinant parathyroid hormone (rPTH) therapy has been evaluated for skeletal repair in animal studies and clinical trials based on its known anabolic effects, but its effects on angiogenesis and fibrosis remain poorly understood. We examined the effects of rPTH therapy on blood vessel formation and osseous integration in a murine femoral allograft model, which caused a significant increase in small vessel numbers, and decreased large vessel formation (p?

SUBMITTER: Dhillon RS

PROVIDER: S-EPMC3540116 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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PTH-enhanced structural allograft healing is associated with decreased angiopoietin-2-mediated arteriogenesis, mast cell accumulation, and fibrosis.

Dhillon Robinder S RS Xie Chao C Tyler Wakenda W Calvi Laura M LM Awad Hani A HA Zuscik Michael J MJ O'Keefe Regis J RJ Schwarz Edward M EM

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20130301 3

Recombinant parathyroid hormone (rPTH) therapy has been evaluated for skeletal repair in animal studies and clinical trials based on its known anabolic effects, but its effects on angiogenesis and fibrosis remain poorly understood. We examined the effects of rPTH therapy on blood vessel formation and osseous integration in a murine femoral allograft model, which caused a significant increase in small vessel numbers, and decreased large vessel formation (p < 0.05). Histology showed that rPTH also ...[more]

PMID: 22991274

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Angiopoietin-2 stimulates blood flow recovery after femoral artery occlusion by inducing inflammation and arteriogenesis.

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| S-EPMC2613177 | biostudies-literature

Intra-oral PTH administration promotes tooth extraction socket healing.

Project description:Intermittent parathyroid hormone (PTH) administration increases systemic and craniofacial bone mass. However, the effect of PTH therapy on healing of tooth extraction sites is unknown. The aims of this study were to determine the effect of PTH therapy on tooth extraction socket healing and to examine whether PTH intra-oral injection promotes healing. The mandibular first molars were extracted in rats, and subcutaneous PTH was administered intermittently for 7, 14, and 28 days. In a second study, maxillary second molars were extracted, and PTH was administered by either subcutaneous or intra-oral injection to determine the efficacy of intra-oral PTH administration. Healing was assessed by micro-computed tomography and histomorphometric analyses. PTH therapy accelerated the entire healing process and promoted both hard- and soft-tissue healing by increasing bone fill and connective tissue maturation. PTH therapy by intra-oral injection was as effective as subcutaneous injection in promoting tooth extraction socket healing. The findings suggest that PTH therapy promotes tooth extraction socket healing and that intra-oral injections can be used to administer PTH.

| S-EPMC3654759 | biostudies-literature

Delayed short-course treatment with teriparatide (PTH(1-34)) improves femoral allograft healing by enhancing intramembranous bone formation at the graft-host junction.

Project description:Clinical management of critical bone defects remains a major challenge. Despite preclinical work demonstrating teriparatide (PTH(1-34)) effectiveness in small animals, inconclusive data from clinical trials have raised questions of dose and regimen. To address this, we completed a comprehensive study in the murine femoral allograft model, to assess the effects of dose (0.4, 4, and 40?µg/kg/day) and various treatment regimens on radiographic, histologic, and biomechanical healing at 2, 4, and 9 weeks. Only the high dose (40?µg/kg) of PTH(1-34) demonstrated significant effects when given daily over 9 weeks. Remarkably, equivalent biomechanical results were obtained with delayed, short treatment from 2 to 6 weeks that did not induce a significant increase in endochondral bone formation and callus volume. In contrast, PTH(1-34) treatment from 1 to 5 weeks postop demonstrated similar osteogenic effects as immediate daily treatment for 9 weeks, but failed to achieve a significant increase in biomechanics at 9 weeks. MicroCT and histologic analyses demonstrated that the 2-week delay in treatment allowed for timely completion of the endochondral phase, such that the prominent effects of PTH(1-34) were enhanced intramembranous bone formation and remodeling at the graft-host junction. These findings support the potential use of PTH(1-34) as an adjuvant therapy for massive allograft healing, and suggest that there may be an ideal treatment window in which a short course is administered after the endochondral phase to promote osteoblastic bone formation and remodeling to achieve superior union with modest callus formation.

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Mast cells condition dendritic cells to mediate allograft tolerance.

Project description:Peripheral tolerance orchestrated by regulatory T cells, dendritic cells (DCs), and mast cells (MCs) has been studied in several models including skin allograft tolerance. We now define a role for MCs in controlling DC behavior ("conditioning") to facilitate tolerance. Under tolerant conditions, we show that MCs mediated a marked increase in tumor necrosis factor (TNF?)-dependent accumulation of graft-derived DCs in the dLN compared to nontolerant conditions. This increase of DCs in the dLN is due to the local production of granulocyte macrophage colony-stimulating factor (GM-CSF) by MCs that induces a survival advantage of graft-derived DCs. DCs that migrated to the dLN from the tolerant allograft were tolerogenic; i.e., they dominantly suppress T cell responses and control regional immunity. This study underscores the importance of MCs in conditioning DCs to mediate peripheral tolerance and shows a functional impact of peripherally produced TNF? and GM-CSF on the migration and function of tolerogenic DCs.

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Decreased expression of calcium-sensing receptor and parafibromin in secondary hyperparathyroidism with an abnormal whole PTH/intact PTH ratio.

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Quantification of massive allograft healing with dynamic contrast enhanced-MRI and cone beam-CT: a pilot study.

Project description:Although massive allografts are widely used for reconstruction of critical defects in long bones caused by tumor or trauma, many will have inadequate long-term outcomes. Toward a tissue engineering solution to this problem, we developed experimental stem cell and gene therapy adjuvants that induce angiogenesis, osteogenesis, and remodeling of the structural allografts. We present data from pilot studies to show the utility of dynamic contrast enhanced MRI (DCE-MRI) to quantify vascularity after femoral osteotomy in a canine femur model and cone beam CT (CB-CT) to quantify bone volume in a patient after composite prosthetic-allograft reconstructive surgery. The results demonstrate our ability to suppress the artifacts generated by the metal implants required to secure massive allografts such that precise quantification of cortical bone revascularization (>10-fold increase at 3 weeks postoperatively) and new bone formation (accurate to about 193 mum(3)) around the graft can be performed longitudinally via DCE-MRI and CB-CT, respectively.

| S-EPMC2577757 | biostudies-other

Therapeutic arteriogenesis by factor-decorated fibrin matrices promotes wound healing in diabetic mice.

Project description:Chronic wounds in type-2 diabetic patients present areas of severe local skin ischemia despite mostly normal blood flow in deeper large arteries. Therefore, restoration of blood perfusion requires the opening of arterial connections from the deep vessels to the superficial skin layer, that is, arteriogenesis. Arteriogenesis is regulated differently from microvascular angiogenesis and is optimally stimulated by high doses of Vascular Endothelial Growth Factor-A (VEGF) together with Platelet-Derived Growth Factor-BB (PDGF-BB). Here we found that fibrin hydrogels decorated with engineered versions of VEGF and PDGF-BB proteins, to ensure protection from degradation and controlled delivery, efficiently accelerated wound closure in diabetic and obese db/db mice, promoting robust microvascular growth and a marked increase in feeding arterioles. Notably, targeting the arteriogenic factors to the intact arterio-venous networks in the dermis around the wound was more effective than the routine treatment of the inflamed wound bed. This approach is readily translatable to a clinical setting.

| S-EPMC9452813 | biostudies-literature

PTH Derivative promotes wound healing via synergistic multicellular stimulating and exosomal activities.

Project description:BackgroundDiabetic wounds are a disturbing and rapidly growing clinical problem. A novel peptide, parathyroid hormone related peptide (PTHrP-2), is assumed as multifunctional factor in angiogenesis, fibrogenesis and re-epithelization. This study aims to test PTHrP-2 efficiency and mechanism in wound healing.MethodsThrough repair phenomenon in vivo some problems were detected, and further research on their mechanisms was made. In vivo therapeutic effects of PTHrP-2 were determined by HE, Masson, microfil and immunohistochemical staining. In vitro direct effects of PTHrP-2 were determined by proliferation, migration, Vascular Endothelial Grown Factor and collagen I secretion of cells and Akt/ Erk1/2 pathway change. In vitro indirect effects of PTHrP-2 was study via exosomes. Exosomes from PTHrP-2 untreated and treated HUVECs and HFF-1 cells were insolated and identified. Exosomes were co-cultured with original cells, HUVECs or HFF-1 cells, and epithelial cells. Proliferation and migration and pathway change were observed. PTHrP-2-HUVEC-Exos were added into in vivo wound to testify its hub role in PTHrP-2 indirect effects in wound healing.ResultsIn vivo, PTHrP-2 exerted multifunctional pro-angiogenesis, pro-firbogenesis and re-epithelization effects. In vitro, PTHrP-2 promoted proliferation and migration of endothelial and fibroblast cells, but had no effect on epithelial cells. Therefore, we tested PTHrP-2 indirect effects via exosomes. PTHrP-2 intensified intercellular communication between endothelial cells and fibroblasts and initiated endothelial-epithelial intercellular communication. PTHrP-2-HUVEC-Exos played a hub role in PTHrP-2 indirect effects in wound healing.ConclusionThese findings of this study indicated that PTHrP-2, a multifunctional factor, could promote wound healing via synergistic multicellular stimulating and exosomal activities.

| S-EPMC7063786 | biostudies-literature

Tubular Overexpression of Angiopoietin-1 Attenuates Renal Fibrosis.

Project description:Emerging evidence has highlighted the pivotal role of microvasculature injury in the development and progression of renal fibrosis. Angiopoietin-1 (Ang-1) is a secreted vascular growth factor that binds to the endothelial-specific Tie2 receptor. Ang-1/Tie2 signaling is critical for regulating blood vessel development and modulating vascular response after injury, but is dispensable in mature, quiescent vessels. Although dysregulation of vascular endothelial growth factor (VEGF) signaling has been well studied in renal pathologies, much less is known about the role of the Ang-1/Tie2 pathway in renal interstitial fibrosis. Previous studies have shown contradicting effects of overexpressing Ang-1 systemically on renal tubulointerstitial fibrosis when different engineered forms of Ang-1 are used. Here, we investigated the impact of site-directed expression of native Ang-1 on the renal fibrogenic process and peritubular capillary network by exploiting a conditional transgenic mouse system [Pax8-rtTA/(TetO)7 Ang-1] that allows increased tubular Ang-1 production in adult mice. Using a murine unilateral ureteral obstruction (UUO) fibrosis model, we demonstrate that targeted Ang-1 overexpression attenuates myofibroblast activation and interstitial collagen I accumulation, inhibits the upregulation of transforming growth factor ?1 and subsequent phosphorylation of Smad 2/3, dampens renal inflammation, and stimulates the growth of peritubular capillaries in the obstructed kidney. Our results suggest that Ang-1 is a potential therapeutic agent for targeting microvasculature injury in renal fibrosis without compromising the physiologically normal vasculature in humans.

| S-EPMC4959721 | biostudies-literature

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