transforming-growth-factor-beta and Lacerations

We report the effects of local administration of osteogenic protein-1 on the biomechanical properties of the overstretched anterior cruciate ligament in an animal model. An injury in the anterior cruciate ligament was created in 45 rabbits. They were divided into three equal groups. In group 1, no treatment was applied, in group II, phosphate-buffered saline was applied around the injured ligament, and in group III, 12.5 microg of osteogenic protein-1 mixed with phosphate-buffered saline was applied around the injured ligament. A control group of 15 rabbits was assembled from randomly-selected injured knees from among the first three groups. Each rabbit was killed at 12 weeks. The maximum load and stiffness of the anterior cruciate ligament was found to be significantly greater in group III than either group 1 (p = 0.002, p = 0.014) or group II (p = 0.032, p = 0.025). The tensile strength and the tangent modulus of fascicles from the ligament were also significantly greater in group III than either group I (p = 0.002, p = 0.0174) or II (p = 0.005, p = 0.022). The application of osteogenic protein-1 enhanced the healing in the injured anterior cruciate ligament, but compared with the control group the treated ligament remained lengthened. The administration of osteogenic protein-1 may have a therapeutic role in treating the overstretched anterior cruciate ligament.

Topics: Animals; Anterior Cruciate Ligament; Anterior Cruciate Ligament Injuries; Biomechanical Phenomena; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Female; Lacerations; Rabbits; Stress, Mechanical; Tensile Strength; Transforming Growth Factor beta; Wound Healing

Degeneration of the rotator cuff is often associated with inflammation of the subacromial bursa and focal mineralization of the supraspinatus tendon. Portions of the supraspinatus tendon distant from the insertion site could transform into fibrous cartilage, causing rotator-cuff tears owing to mechanical instability. Indirect evidence is presented to link this pathology to ectopic production and secretion of bioactive bone morphogenetic proteins (BMPs) from sites within the subacromial bursa. Surgically removed specimens of subacromial bursa tissue from patients with chronic tears of the rotator cuff were analyzed by immunohistochemistry and reverse transcription-PCR. Bioactive BMP was detected in bursa extracts by a bioassay based on induction of alkaline phosphatase in the osteogenic/myogenic cell line C2C12. Topical and differential expression of BMP-2/4 and BMP-7 mRNA and protein was found in bursa tissue. The bioassay of C2C12 cells revealed amounts of active BMP high enough to induce osteogenic cell types, and blocking BMP with specific antibodies or soluble BMP receptors Alk-3 and Alk-6 abolished the inductive properties of the extract. Sufficient information was gathered to explain how ectopic expression of BMP might induce tissue transformation into ectopic bone/cartilage and, therefore, promote structural degeneration of the rotator cuff. Early surgical removal of the subacromial bursa might present an option to interrupt disease progression.

Topics: Adult; Aged; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Bursa, Synovial; Cells, Cultured; Chronic Disease; Cytokines; Extracellular Matrix Proteins; Histocytochemistry; Humans; Immunohistochemistry; Lacerations; Middle Aged; RNA, Messenger; Rotator Cuff Injuries; Transforming Growth Factor beta

No studies have been conducted to clarify the in vivo effect of growth factor application on healing in the injured anterior cruciate ligament.. Administration of exogenous growth factors significantly increases the structural properties of the injured anterior cruciate ligament.. Controlled laboratory study.. Thirty-six rabbits were randomly divided into 4 groups of 9 animals each after an overstretched injury was made in the right anterior cruciate ligament. In group 1, no treatment was applied around the injured anterior cruciate ligament. In group 2, 0.2 mL fibrin sealant was applied around it. In group 3, 4 ng transforming growth factor-beta1 mixed with 0.2 mL fibrin sealant was applied. In group 4, 20 microg platelet-derived growth factor-BB mixed with 0.2 mL fibrin sealant was applied. Each rabbit was sacrificed at 12 weeks after the surgery. In addition, 9 knees randomly harvested from all the left knees were used to obtain normal control data. The femur-anterior cruciate ligament-tibia complex specimens were biomechanically and histologically evaluated.. Concerning the maximum load and the stiffness, group 3 was significantly greater than groups 1 and 2, whereas there were no significant differences among groups 1, 2, and 4. Groups 1, 2, 3, and 4 were significantly lower than the control group.. The application of 4 ng transforming growth factor-beta1 significantly enhances healing in the injured anterior cruciate ligament.. Administration of certain growth factors is of value to be studied as one of the future therapeutic options for the overstretched anterior cruciate ligament injury.

Topics: Animals; Anterior Cruciate Ligament Injuries; Becaplermin; Biomechanical Phenomena; Female; Fibrin Tissue Adhesive; Lacerations; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Rabbits; Recombinant Proteins; Rupture; Tensile Strength; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

Growth factors, transforming growth factor beta (TGF-beta), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF), are critical components of the cutaneous wound healing process. Little is known, however, about the expression of these growth factors in normal flexor tendon healing. In this study, we wished to examine which of these growth factors are present at 10 days following tendon injury in a canine flexor tendon repair model. Using immunohistochemical analysis, we found positive staining for all growth factors in both timing groups. TGF-beta was detected around the repair site and proximal to it. PDGF-AA, PDGF-BB and VEGF appeared in the whole tendon section following repair. EGF, IGF and bFGF were not seen in tenocytes but were present in inflammatory cells surrounding the repair site. These findings provide evidence that TGF-beta, EGF, PDGF-AA, PDGF-BB, IGF, bFGF and VEGF are all expressed at 10 days after tendon injury but by different cell types and in different locations. The time course of growth factor expression is an important element in wound healing, and a better understanding of where and when such factors are expressed may help in the development of methods to manipulate this expression, accelerate healing, and reduce adhesions.

Topics: Animals; Dogs; Epidermal Growth Factor; Immunohistochemistry; Lacerations; Somatomedins; Tendons; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Muscle injuries are a common problem in sports medicine. Skeletal muscle can regenerate itself, but the process is both slow and incomplete. Previously we and others have used growth factors to improve the regeneration of muscle, but the muscle healing was impeded by scar tissue formation. However, when we blocked the fibrosis process with decorin, an antifibrosis agent, we improved the muscle healing. Here we show that gammainterferon (gammaINF)--a cytokine that inhibits the signaling of transforming growth factor beta1 (TGFbeta1), a fibrotic stimulator--reduces fibrosis formation and improves the healing of lacerated skeletal muscle. With gammaINF treatment, the growth rate of muscle-derived fibroblasts was reduced and the level of fibrotic protein expression induced by TGFbeta1 (including TGFbeta1, vimentin, and alpha-smooth muscle actin) was down-regulated in vitro. In a mouse laceration model, the area of fibrosis decreased when gammaINF was injected at either 1 or 2 weeks after injury. More importantly, the injection of gammaINF at either 1 or 2 weeks post-injury was found to improve muscle function in terms of both fast-twitch and tetanic strength. This study demonstrates that gammaINF is a potent antifibrosis agent that can improve muscle healing after laceration injury.

Topics: Animals; Cells, Cultured; Dose-Response Relationship, Drug; Down-Regulation; Fibroblasts; Fibrosis; Injections, Intramuscular; Interferon-gamma; Lacerations; Mice; Mice, Inbred C57BL; Muscle Contraction; Muscle, Skeletal; Myoblasts; Regeneration; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

A rabbit annular laceration model was used to investigate intervertebral disc gene expression in normal and lacerated discs.. To determine and compare the pattern of expression of potentially important genes in normal and lacerated discs and to determine if the changes in gene expression were similar to human degenerative discs.. Little is known regarding gene expression in normal or degenerating disc tissue.. Eighteen rabbits were subjected to annular laceration of the L1-L2 and L2-L3 discs while two rabbits served as sham controls. Control and lacerated discs were harvested 1 week, 3 weeks, and 6 weeks following surgery and subjected to histologic examination and gene expression analysis using the reverse transcription-polymerase chain reaction (RT-PCR). The genes studied included collagen Type I (Col I), collagen Type II (Col II), decorin, fibronectin (FN), interleukin-1a (IL-1alpha), bone morphogenetic protein 2 (BMP-2), Fas, matrix metalloproteinase 1 (MMP-1), matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 13 (MMP-13), and tumor necrosis factor (TNF). Expression levels of each gene were normalized to that of glyceraldehyde-3-phosphate dehydrogenase (GADPH), a constitutively expressed gene.. Histology confirmed progressive degeneration of the discs over the 6-week study period. Different patterns of gene expression were observed in control and lesioned discs. Annular laceration caused a marked upregulation (two- to eightfold) of the expression of Col I, Col II, FN, MMP-1, MMP-9, MMP-13, and Fas genes, whereas that of BMP-2, IL-1alpha, and TNF genes was unaffected. Expression of the decorin gene was downregulated approximately sixfold after annular laceration.. Annular laceration in this animal model resulted in marked changes in gene expression. Upregulation of gene expression was observed for some molecules found at high concentration in human degenerated discs, suggesting similarities to human disc degeneration at the molecular level. This supports the need for further study of the genes found to be activated by annular laceration.

Topics: Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Collagen; Collagenases; Decorin; Extracellular Matrix Proteins; fas Receptor; Fibronectins; Gene Expression Profiling; Interleukin-1; Intervertebral Disc; Lacerations; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 13; Matrix Metalloproteinase 9; Models, Animal; Proteoglycans; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha