transforming-growth-factor-beta and Wounds--Penetrating

Despite significant advances in the treatment of Crohn's disease (CD), most patients still develop stricturing or penetrating complications that require surgical resections. We performed a systematic review of mechanisms and potential treatments for tissue damage lesions in CD patients.. We searched the PubMed, MBASE, and Cochrane databases from January 1960 to July 2017 for full-length articles on CD, fibrosis, damage lesions, mesenchymal stem cells, and/or treatment. We also searched published conference abstracts and performed manual searches of all reference lists of relevant articles.. Mechanisms of intestinal damage in patients with CD include fibroblast proliferation and migration, activation of stellate cells, recruitment of intestinal or extra-intestinal fibroblast, and cell trans-differentiation. An altered balance of metalloproteinases and tissue inhibitors of metalloproteinases might contribute to fistula formation. Treatment approaches that reduce excessive transforming growth factor beta (TGFB) activation might be effective in treating established intestinal damage. Stem cell therapies have been effective in tissue damage lesions in CD. Particularly, randomized controlled trials have shown local injections of mesenchymal stem cells to heal perianal fistulas.. In a systematic review of mechanisms and treatments of bowel wall damage in patients with CD, we found a need to test drugs that reduce TGFB and increase healing of transmural damage lesions and to pursue research on local injection of mesenchymal stem cells.

Topics: Cell- and Tissue-Based Therapy; Constriction, Pathologic; Crohn Disease; Humans; Transforming Growth Factor beta; Treatment Outcome; Wounds, Penetrating

Topics: Animals; Cartilage, Articular; Drug Carriers; Fibroblast Growth Factor 2; Growth Substances; Humans; Insulin-Like Growth Factor I; Species Specificity; Transforming Growth Factor beta; Wound Healing; Wounds, Nonpenetrating; Wounds, Penetrating

Many researches have been undergone to hasten the natural wound healing process. In this study, several Hibiscus species (leaves) were extracted with petroleum ether, methanol, and their mucilage was separated. All the tested species extracts were assessed for their viability percentage using the water-soluble tetrazolium. H.syriacus was the plant of choice to be incorporated in a new drug delivery system and evaluated for its wound healing activity. H.syriacus petroleum ether extract (PEE) showed a high percentage of palmitic and oleic acids while its mucilage demonstrated high glucosamine and galacturonic acid. It was selected to be formulated and pharmaceutically evaluated into three different composite sponges using chitosan in various ratios. Fourier-transformed infrared spectroscopy investigated the chemical interaction between the utilized sponges' ingredients. Morphological characteristics were evaluated using scanning electron microscopy. H.syriacus composite sponge of mucilage: chitosan (1:5) was loaded with three different concentrations of PEE. Medicated formulations were assessed in rat model of excision wound model. The wound healing ability was clearly proved by the clinical acceleration, histopathological examination, and modulation of correlated inflammatory parameters as tumor necrosis factor in addition to vascular endothelial growth factor suggesting a promising valuable candidate that supports the management of excision wounds using single-dose preparation.

Topics: Administration, Cutaneous; Animals; Cell Line; Chitosan; Disease Models, Animal; Hibiscus; Humans; Inflammation Mediators; Lipids; Male; Plant Extracts; Rats, Wistar; Re-Epithelialization; Skin; Surgical Sponges; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Wound Healing; Wounds, Penetrating

Post-traumatic large-surface or deep wounds often cannot progress to reepithelialisation because they become irresponsive in the inflammatory stage, so intervention is necessary to provide the final sealing epidermis. Previously we have shown that Amniotic Membrane (AM) induced a robust epithelialisation in deep traumatic wounds.. To better understand this phenomenon, we used keratinocytes to investigate the effect of AM on chronic wounds. Using keratinocytes, we saw that AM treatment is able to exert an attenuating effect upon Smad2 and Smad3 TGFß-induced phosphorylation while triggering the activation of several MAPK signalling pathways, including ERK and JNK1, 2. This also has a consequence for TGFß-induced regulation on cell cycle control key players CDK1A (p21) and CDK2B (p15). The study of a wider set of TGFß regulated genes showed that the effect of AM was not wide but very concrete for some genes. TGFß exerted a powerful cell cycle arrest; the presence of AM however prevented TGFß-induced cell cycle arrest. Moreover, AM induced a powerful cell migration response that correlates well with the expression of c-Jun protein at the border of the healing assay. Consistently, the treatment with AM of human chronic wounds induced a robust expression of c-Jun at the wound border.. The effect of AM on the modulation of TGFß responses in keratinocytes that favours proliferation together with AM-induced keratinocyte migration is the perfect match that allows chronic wounds to move on from their non-healing state and progress into epithelialization. Our results may explain why the application of AM on chronic wounds is able to promote epithelialisation.

Topics: Amnion; Animals; Cell Cycle; Cell Proliferation; Cells, Cultured; Epithelial Cells; Humans; Keratinocytes; Lung; MAP Kinase Signaling System; Mink; Phosphorylation; Proto-Oncogene Proteins c-jun; Re-Epithelialization; Smad2 Protein; Transforming Growth Factor beta; Wound Healing; Wounds, Penetrating

Duodenal injuries, though rare, carry high rates of morbidity and mortality. The aim of the study was to evaluate the healing of the duodenal wall with the use of a Small Intestinal Submucosa (SIS) patch.. We studied 40 Wistar-Albino rats divided into two groups. In group A, we created a small defect in the duodenal wall, which was immediately covered with a SIS patch. In group B, the SIS patch was sutured over the defect after 6-8 hours, in order to induce peritonitis. The animals of both groups were sacrificed after 2, 6, 12 and 16 weeks respectively. In addition, we studied the immunohistochemical expression of TGF-β, which is a major constituent of SIS, and plays a central role in the healing process.. Histology showed progressive development of the layers of the duodenal wall over the patch as early as the 2nd week in some of the animals of group A. Mucosa developed later on in the animals of group B, presumably due to the more intense inflammation elicited by peritonitis. Expression of TGF-β was initially more pronounced in the epithelial cells of the regenerating mucosa of animals of group A, but it was maintained in higher levels in the animals of group B, which showed delayed mucosa degeneration.. SIS appears to be both efficient and safe for the management of duodenal trauma. TGF-β seems to play an important role in the healing process, inducing regeneration of the stroma, and controlling epithelial growth.

Topics: Animals; Duodenum; Intestinal Mucosa; Peritonitis; Rats; Rats, Wistar; Time Factors; Transforming Growth Factor beta; Wound Healing; Wounds, Penetrating

The aim of the present investigation was to evaluate transforming growth factor β (TGF-β) expression on cutaneous wounds in rodents treated or not treated with LED light.. TGF-β is a multifunctional cytokine that presents a central action during tissue repair. Although several studies both in vitro and in vivo have shown that LED phototherapy influences tissue repair, a full understanding of the mechanisms involved in its usage, such as in the modulation of some growth factors, remains unclear.. Under general anesthesia, 24 young adult male Wistar rats weighing 200-250 g had one excisional wound created on the dorsum of each, and were randomly distributed into two groups: G0 (Control) and G1 (LED, λ700 ± 20 nm, 16 mW, SAEF = 5 J/cm(2), Illuminated Area = 2 cm(2), 8 mWcm(2), 626 s) Each group was subdivided into three subgroups according to the animal death timing (2, 4, and 6 days). LED phototherapy started immediately after surgery and was repeated every other day during the experimental time. Following animal death, specimens were removed, routinely processed to wax, cut and immunomarked with polyclonal anti-TGF-β, and underwent histological analysis by light microscopy. The mean area of expression of each group was calculated. The data were statistically analyzed using ANOVA and Tukey's test.. The area of the expression of TGF-β on LED-irradiated animals was significantly smaller than on controls at day 2 (p = 0.013). No significant difference was found at later times. It is concluded that the use of LED light, at these specific parameters, caused an inhibition of the expression of TGF-β at an early stage of the healing process.

Topics: Animals; Disease Models, Animal; Granulation Tissue; Male; Phototherapy; Rats; Rats, Wistar; Transforming Growth Factor beta; Wound Healing; Wounds, Penetrating

Collagen membranes have been developed to overcome the problem of limited availability of skin grafts. Vascularization and restricted functional epithelization limit the success of bioartificial constructs.. To compare the vascularization, epithelization, and integration of a porcine collagen I/III membrane with that of split-thickness skin grafts on skin wounds.. In 21 adult pigs, full-thickness skin defects on the rear side of the ear healed by split-thickness skin grafting, by covering with the membrane, or by free granulation. Skin samples on postoperative days 1, 3, 7, 14, 21, and 28 were evaluated histologically (hematoxylin-eosin, Sirius Red) and using immunohistochemistry (cytokeratin 5/6, transforming growth factor beta receptor (TGFbetaR-III) and immunoblot (TGFbeta(1,3), Smad2/3). Epithelial thickness and TGFbetaR-III-positive capillary area were quantitatively assessed.. Epithelization and vascularization in the membrane group were not significantly different from in the group treated with a split-thickness skin graft. Free granulation showed significantly slower epithelization and vascularization (p<.05). TGFbeta(1) and Smad2/3 complex expression were high during free granulation. Matrix was distinguishable until day 7.. This membrane serves as a suitable full-thickness dermal substitute, because the membrane is vascularized faster than free granulation tissue and enables early epithelization.

Topics: Animals; Collagen Type I; Collagen Type III; Dermis; Neovascularization, Physiologic; Skin, Artificial; Smad Proteins, Receptor-Regulated; Swine; Tissue Scaffolds; Transforming Growth Factor beta; Wound Healing; Wounds, Penetrating

Despite numerous studies that have investigated the cellular and molecular mechanisms underlying scar formation, this process still remains poorly understood. The importance of transforming growth factor-beta (TGF-beta) in these processes has been well recognized, and this study sought to define the temporal expression of the key members in this pathway in a well-established, clinically relevant, rabbit ear model of hypertrophic scarring.. Seven-millimeter (hypertrophic) and 5-mm (nonhypertrophic) punch wounds were made on the ears of 12 rabbits. Wounds were harvested at days 0, 7, 15, 28, and 40.. There were no appreciable histologic differences between the 5- and 7-mm wounds at days 7 and 15. At day 28, however, the 7-mm scars were considerably more hypertrophic compared with the 5-mm control scars (p<0.001). The mRNA levels of TGF-beta1 and collagen Ialpha2 were notably higher in the hypertrophic 7-mm scars at day 28 than in the nonhypertrophic 5-mm scars (p<0.03). Although not pronounced, levels of TGF-beta2 were higher in the hypertrophic scars. There were no other statistically significant differences between the 7- and 5-mm scars.. Elevated levels of TGF-beta1, and possibly TGF-beta2, are associated with hypertrophic scar formation.

Topics: Animals; Cicatrix, Hypertrophic; Disease Models, Animal; Ear; Female; Rabbits; Receptors, Transforming Growth Factor beta; RNA, Messenger; Smad Proteins; Time Factors; Transforming Growth Factor beta; Wound Healing; Wounds, Penetrating

Fetal rat skin transitions from scarless fetal-type repair to adult-type repair with scar between day 16 (E16) and day 18 (E18) of gestation (term = 21.5 days). Deficient transforming growth factor (TGF)-beta 1 and -beta 2 injury response has been proposed as a mechanism for scarless fetal-type repair. However, previous fetal studies have inconsistently reported the degree of TGF-beta induction after injury. To minimize developmental variables in fetal versus adult TGF-beta regulation, we narrowed our study to wounded fetal animals. We hypothesize that TGF-beta ligand and receptor expression will be differentially regulated during the transition from early gestation (E16) wounds manifesting scarless fetal-type repair to late gestation (E19) wounds manifesting adult-type repair with scar. In this study, decreased and rapidly cleared TGF-beta 1 and -beta 2 expression accompanied by increased and prolonged TGF-beta 3 levels in wounded E16 animals correlated with organized collagen deposition. In contrast, increased and prolonged TGF-beta 1 and -beta 2 expression accompanied by decreased and delayed TGF-beta 3 expression in wounded E19 animals correlated with disorganized collagen architecture. Similarly, expression of TGF-beta receptors type I and II were also increased or prolonged in E19 animals. Our results implicate increased TGF-beta 1, -beta 2, and decreased TGF-beta 3 expression, as well as increased type I and II receptor expression in late gestation fetal scar formation.

Topics: Animals; Collagen; Embryonic and Fetal Development; Eosine Yellowish-(YS); Female; Hematoxylin; Immunohistochemistry; Microscopy, Confocal; Prenatal Injuries; Protein Isoforms; Rats; Rats, Sprague-Dawley; Receptors, Transforming Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin; Transforming Growth Factor beta; Wound Healing; Wounds, Penetrating

Chronic wounds are a major clinical problem with notable morbidity. Treatment is usually supportive and results in significant healthcare expenditures. It is estimated that 1.25 million people are burned each year in the United States and that 6.5 million have chronic skin ulcers caused by pressure, venous stasis, or diabetes mellitus. Wound healing is a complex and lengthy process, often taking up to 12 months to complete. The cost of treating poorly healing foot wounds in the United States has been estimated at $1 billion per year. A number of topical commercial products have become available to provide an optimal environment for problematic open wounds. Topical platelet-derived growth factor (PDGF)-BB has proven effective in improving healing in impaired wounds but has the disadvantage of requiring large and repeated doses. More recently, investigators have focused on the possibility of inserting genes encoding for growth factors such as PDGF-BB into the cells participating in the wound-healing response. This approach offers the potential of single-dose growth factor treatment of chronic wounds. There are several approaches for gene insertion, including viral vectors, gene guns, and electroporation. This article reviews the strategies and potential of these approaches, with a focus on electroporation.

Topics: Animals; Chronic Disease; Electroporation; Fibroblast Growth Factors; Gene Transfer Techniques; Genetic Therapy; Humans; Platelet-Derived Growth Factor; Transforming Growth Factor beta; Wound Healing; Wounds, Penetrating

The isoforms of transforming growth factor beta (TGF-beta) have been shown to be deficient in models of impaired wound healing. Exogenous application of the growth factor to enhance healing as been investigated. TGF-beta1 has been shown to enhance incisional wound strength, but to be dependent on the vehicle used to carry the cytokine. Because TGF-beta2 has shown safety in human trials of chronic wound healing, this study evaluates TGF-beta2 in acute incisional healing using a variety of vehicles.. Using an acute incisional wound model in healthy rats, rhTGF-beta2 was suspended in various vehicles including fibrin sealant (normal commercial concentration), fibrin sealant (dilute concentration), phosphate buffered saline/serum albumin, and a carboxymethycellulose gel. A single dose of the agent was instilled into the incisions at the time of wound closure and breaking strength analyses and histology performed periodically from days 3-14.. TGF-beta2 enhanced the gain of incisional strength in all vehicles during the first two weeks of healing. This was most noticeable by day three with the carboxymethycellulose gel, but by day 7 with the other vehicles. Like reports with TGF-beta1, TGF-beta2 accelerated the gain of wound strength by about three days by day 11. Normal density fibrin sealant delayed incisional healing; whereas, the other vehicles without TGF-beta2 had no significant effect.. The use of TGF-beta2 appears to be of value in increasing incisional wound strength in the first 14 days post-wounding in healthy rats and this effect is demonstrated in a variety of vehicles. These data support the hypothesis that the "normal" incisional wound healing curve can he shifted to the left. Shortening the time for gain of incisional wound strength may have potential clinical use.

Topics: Animals; Disease Models, Animal; Fibrin Tissue Adhesive; Immunosuppressive Agents; Male; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Transforming Growth Factor beta2; Treatment Outcome; Wound Healing; Wounds, Penetrating

Transforming growth factor (TGF)-beta regulates wound repair and scarring in an isoform-specific fashion. TGF-beta is produced in a latent form, and its activation is a critical regulatory step controlling the bioactivity of this growth factor. To date, it has been impossible to determine latent TGF-beta activation in vivo due to a lack of quantitative assays. We describe here a semiquantitative modification of the plasminogen activator inhibitor-1/luciferase bioassay (PAI/L assay) for TGF-beta, which we used to determine active and latent TGF-beta isoforms in frozen sections of rat wound tissue. We found that significant amounts of latent TGF-beta were rapidly activated upon wounding (38% of the total TGF-beta at 1 hour after wounding). A second peak of active TGF-beta (17% of total) occurred at 5 days after wounding. The predominant isoforms were TGF-beta1 and -2 with only minor amounts of TGF-beta3 present. This is the first TGF-beta bioassay allowing semiquantitative determination of active and latent isoforms present in vivo, and our results document the significance and temporal regulation of latent TGF-beta isoform activation in wound repair.

Topics: Animals; Biological Assay; Frozen Sections; Hot Temperature; Isomerism; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Skin; Transforming Growth Factor beta; Wound Healing; Wounds, Penetrating

The transforming growth factor-betas (TGF-betas) are potent fibrogenic factors implicated in numerous central nervous system (CNS) pathologies in which fibrosis and neural dysfunction are causally associated. In this study, we aim to limit the fibrogenic process in a model of CNS scarring using a recombinant human monoclonal antibody, derived from phage display libraries and specific to the active form of the TGF-beta2 isoform. The implicit inference of the work was that, as such antibodies are potential pharmacological agents for the treatment of human CNS fibrotic diseases, validation of efficacy in a mammalian animal model is a first step towards this end. Treatment of cerebral wounds with the anti-TGF-beta2 antibody led to a marked attenuation of all aspects of CNS scarring, including matrix deposition, formation of an accessory glial-limiting membrane, inflammation and angiogenesis. For example, in the wound, levels of: (i) the connective tissue components fibronectin, laminin and chondroitin sulphate proteoglycan; and (ii) wound-responsive cells including astrocytes and macrophages/microglia, were markedly reduced. Our findings suggest that such synthetic anti-fibrotic TGF-beta antibodies are potentially applicable to a number of human CNS fibrotic diseases to arrest the deposition of excessive extracellular matrix components, and maintain and/or restore functional integrity.

Topics: Animals; Antibodies, Monoclonal; Brain Injuries; Cicatrix; Female; Humans; Neuroglia; Rats; Rats, Wistar; Recombinant Proteins; Transforming Growth Factor beta; Wounds, Penetrating

The transforming growth factor-betas (TGF-betas) are potent fibrogenic factors implicated in numerous CNS pathologies in which fibrosis and neural dysfunction are causally associated. In this study, we aimed to demonstrate significant inhibition of fibrogenesis, glial scarring, and inflammation in penetrating incisional wounds of the rat brain using the proteoglycan decorin, which effectively inhibits TGF-beta activity. Adult rats were assigned to two treatment groups each receiving 14 daily intraventricular injections of 10 microliter total volume of: (i) saline plus 0.3% autologous rat serum = 30 microgram protein); or (ii) saline plus 30 microgram recombinant human decorin. On day 0 of the experiment, a stereotactically defined unilateral incisional lesion was placed through the cerebral cortex into the lateral ventricle and, after 14 days, brains were processed for immunohistochemical analysis of the lesion site. Specific antibodies were used to visualize the deposition within the wound of matrix molecules and the extent and nature of reactive astrocytosis and inflammation. Quantitative and qualitative image analysis of the fibrous scar was performed in sections from a defined anatomical plane through the wound to detect the antifibrotic effects of decorin treatment. Treatment of wounds with decorin led to a marked attenuation of all aspects of CNS scarring including matrix deposition, formation of an accessory glial limiting membrane, and inflammation. Our findings suggest that decorin is potentially applicable to a number of human CNS fibrotic diseases to arrest the deposition of excessive extracellular matrix components and maintain and/or restore functional integrity.

Topics: Animals; Brain Injuries; Cerebral Cortex; Cerebral Ventricles; Cicatrix; Decorin; Extracellular Matrix Proteins; Female; Fibronectins; Glial Fibrillary Acidic Protein; Gliosis; Humans; Injections, Intraventricular; Laminin; Macrophages; Microglia; Proteoglycans; Rats; Rats, Wistar; Recombinant Proteins; Transforming Growth Factor beta; Wounds, Penetrating

In order to fulfill its many functions as the selective interface between maternal and fetal circulations it is imperative that the human placenta remains intact and in good operational order. That damage of some sort occurs during its short but extremely active life seems inevitable given the dynamic environment in which the placenta exists, and evidence has accumulated that disruption is indeed a regular event. The implications of such damage, one could speculate, may impact on functions such as transport and hormone secretion as well as mutual protection against attack by maternal and fetal immune systems. Consequently, it would seem a theoretical necessity for discontinuities in the placenta surface to be repaired as soon as possible. We have used a combination of ex vivo observation, in vitro modelling, immunohistochemistry and correlative microscopy to provide evidence for a wound response in the placenta and to begin dissecting the detail of how this may operate. Evidence for small lesions caused by fusion and subsequent tearing of the syncytiotrophoblast in vivo, as well as plugging of such wounds by underlying cells is shown. We also identify a putative role for migratory cytotrophoblasts in the healing of larger scale injuries and demonstrate that certain molecules, common to wound repair in other tissues, appear to be involved in placenta repair also. Taken together these results clearly show that the human placenta is capable of a degree of self-maintenance by activating what appears to be an endogenous wound healing mechanism.

Topics: Chorionic Villi; Female; Humans; Lipopolysaccharide Receptors; Microscopy, Electron, Scanning; Placenta; Pregnancy; Pregnancy Trimester, First; Tenascin; Transforming Growth Factor beta; Wound Healing; Wounds, Penetrating

Dehiscence of colonic anastomoses is a multifactorial phenomenon. One mechanism by which this can occur is a deficiency of colonic submucosal collagen. Peptide growth factors (PGFs) have been shown to play a role in the synthesis, deposition, and maturation of collagen. Specifically, in tissues other than the colon, the transforming growth factor-beta (TGF-beta1) gene has been shown to be temporally associated with expression of the procollagen gene. This study examines the temporal expression of the TGF-beta1, epidermal growth factor (EGF), and platelet-derived growth factor B (PDGF-BB) genes and their temporal relationship to the expression of the procollagen type 1 (PROC I) gene.. Forty-eight Sprague-Dawley rats underwent transection of the descending colon with primary anastomosis. Perianastomotic colonic tissue was harvested on Day 0 and postoperative days 3, 5, 6, 7, and 14. Colonic tissue was analyzed using semiquantitative reverse transcriptase-polymerase chain reaction and primers specific for the TGF-beta1, EGF, and PDGF-B growth factors. Relative expression ratios of PGFs and PROC I genes were calculated versus a constitutive gene.. The data show that although all three of the PGFs genes were expressed in healing postoperative colonic tissue, only TGF-beta1 showed a significant increase in its level of expression versus a constitutive gene from a mean ratio of 0.4 +/- 0. 08 on Day 0 to a mean ratio of 1.9 +/- 0.27 on Day 7 (P < 0.0001 by ANOVA). The PROC I gene also showed a significant increase in expression (P < 0.001 by ANOVA) in the postoperative period which temporally correlated with the increase in the expression of the TGF-beta1 gene (r = 0.89, P < 0.05).. The temporal correlation between an increase in the gene expression of TGF-beta1 and PROC I is initial evidence that that TGF-beta1 plays a significant role in collagen metabolism in a healing colonic anastomosis.

Topics: Animals; Becaplermin; Colon; Epidermal Growth Factor; Gene Expression Regulation; Male; Platelet-Derived Growth Factor; Procollagen; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Transforming Growth Factor beta; Wound Healing; Wounds, Penetrating

By means of monoclonal anti-bone morphogenetic protein 2 immunohistochemical methods, endogenous bone morphogenetic protein was observed in the process of generation of heterotopic bone in experimental punch holes in the rabbit's ear. In repair of the punch hole, dermis, subcutaneous connective tissue, and perichondrium proliferated, hypertrophied, and differentiated in the rim within 2 weeks. By 3 to 4 weeks, epidermis grew centripetally down into and across the dorsal and ventral openings and sealed the punch hole. A blastema-like structure consisting of a condensation of the mesenchymal type cells covered the cut ends of the elastic cartilage. The condensation differentiated into chondro-osteoprogenitor cells and hyaline cartilage within 4 to 5 weeks. Within 4 to 6 weeks, sprouting capillaries, macrophages, and monocytes resorbed and replaced hyaline cartilage with a perichondral ring of bone. Anti-bone morphogenetic protein 2 appeared first in the perichondrium, then in the condensation, and later in the chondro-osteoprogenitor cells. A basic assumption was that latent non-reactive bone morphogenetic protein was converted to the anti-bone morphogenetic protein 2-reactive form by injury, inflammation, and proteolysis. The reactive form and various other local factors contributed the temporal and spatial constraints of a morphogenetic field for development of heterotopic bone. The receptors and mechanism of bone morphogenetic protein signal transduction are unknown.

Topics: Animals; Antibodies, Monoclonal; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Capillaries; Cell Differentiation; Cell Division; Connective Tissue; Ear Cartilage; Ear, External; Epidermis; Hyalin; Hypertrophy; Immunohistochemistry; Inflammation; Macrophages; Mesoderm; Monocytes; Ossification, Heterotopic; Protein Denaturation; Rabbits; Signal Transduction; Skin; Stem Cells; Transforming Growth Factor beta; Wound Healing; Wounds, Penetrating