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Systemic administration of IGF-I enhances healing in collagenous extracellular matrices: evaluation of loaded and unloaded ligaments.

Provenzano PP, Alejandro-Osorio AL, Grorud KW, Martinez DA, Vailas AC, Grindeland RE, Vanderby R - BMC Physiol. (2007)

Bottom Line: Tissues from ambulatory animals receiving only saline had significantly greater strength than tissue from saline receiving hindlimb unloaded animals.Addition of GH alone did not have a significant effect on either group, while addition of GH+IGF-I significantly improved force, stress, and modulus values in MCLs from hindlimb unloaded animals.Growth hormone alone did not result in any significant improvement contrary to our hypothesis, while GH + IGF-I produced remarkable improvement in hindlimb unloaded animals.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept. of Biomedical Engineering, University of Wisconsin, Madison, WI, USA. ppproven@wisc.edu

ABSTRACT

Background: Insulin-like growth factor-I (IGF-I) plays a crucial role in wound healing and tissue repair. We tested the hypotheses that systemic administration of IGF-I, or growth hormone (GH), or both (GH+IGF-I) would improve healing in collagenous connective tissue, such as ligament. These hypotheses were examined in rats that were allowed unrestricted activity after injury and in animals that were subjected to hindlimb disuse. Male rats were assigned to three groups: ambulatory sham-control, ambulatory-healing, and hindlimb unloaded-healing. Ambulatory and hindlimb unloaded animals underwent surgical disruption of their knee medial collateral ligaments (MCLs), while sham surgeries were performed on control animals. Healing animals subcutaneously received systemic doses of either saline, GH, IGF-I, or GH+IGF-I. After 3 weeks, mechanical properties, cell and matrix morphology, and biochemical composition were examined in control and healing ligaments.

Results: Tissues from ambulatory animals receiving only saline had significantly greater strength than tissue from saline receiving hindlimb unloaded animals. Addition of IGF-I significantly improved maximum force and ultimate stress in tissues from both ambulatory and hindlimb unloaded animals with significant increases in matrix organization and type-I collagen expression. Addition of GH alone did not have a significant effect on either group, while addition of GH+IGF-I significantly improved force, stress, and modulus values in MCLs from hindlimb unloaded animals. Force, stress, and modulus values in tissues from hindlimb unloaded animals receiving IGF-I or GH+IGF-I exceeded (or were equivalent to) values in tissues from ambulatory animals receiving only saline with greatly improved structural organization and significantly increased type-I collagen expression. Furthermore, levels of IGF-receptor were significantly increased in tissues from hindlimb unloaded animals treated with IGF-I.

Conclusion: These results support two of our hypotheses that systemic administration of IGF-I or GH+IGF-I improve healing in collagenous tissue. Systemic administration of IGF-I improves healing in collagenous extracellular matrices from loaded and unloaded tissues. Growth hormone alone did not result in any significant improvement contrary to our hypothesis, while GH + IGF-I produced remarkable improvement in hindlimb unloaded animals.

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Representative tissue sections taken from the midsubstance region of control normal tissue (Sham) and scar tissues (Saline, GH, IGF-I, GH+IGF-I). The longitudinal axis of the ligament is from the top left to bottom right of each image (200X). Tissues from sham control (Sham) animals have the characteristic crimp pattern and aligned fibroblasts associated with normal tissue. Examination of scar tissue from ambulatory healing animals (Amb + Sal) revealed typical scar morphology with matrix disorganization and hypercellularity. In contrast to ambulatory animals, hindlimb unloaded (HU + Sal) animals showed abnormal scar formation with pockets of cell clusters and misaligned collagen fibers creating defects and voids by not connecting. Examination of extracellular matrices from GH treated animals revealed no improvement in matrix organization in tissues from ambulatory (Amb + GH) or hindlimb unloaded (HU + GH) animals. However, animals treated with IGF-I showed extensively increased matrix density and substantially improved matrix alignment in tissues from ambulatory (Amb + IGF) and hindlimb unloaded (HU + IGF) animals; indicating a considerable improvement in the matrix structure in animals treated with IGF-I. Animals that were treated with both GH and IGF-I showed similar improvement to that seen with IGF-I in unloaded tissues (HU + GH + IGF) but showed no improvement in ambulatory tissues (Amb + GH + IGF).
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Figure 4: Representative tissue sections taken from the midsubstance region of control normal tissue (Sham) and scar tissues (Saline, GH, IGF-I, GH+IGF-I). The longitudinal axis of the ligament is from the top left to bottom right of each image (200X). Tissues from sham control (Sham) animals have the characteristic crimp pattern and aligned fibroblasts associated with normal tissue. Examination of scar tissue from ambulatory healing animals (Amb + Sal) revealed typical scar morphology with matrix disorganization and hypercellularity. In contrast to ambulatory animals, hindlimb unloaded (HU + Sal) animals showed abnormal scar formation with pockets of cell clusters and misaligned collagen fibers creating defects and voids by not connecting. Examination of extracellular matrices from GH treated animals revealed no improvement in matrix organization in tissues from ambulatory (Amb + GH) or hindlimb unloaded (HU + GH) animals. However, animals treated with IGF-I showed extensively increased matrix density and substantially improved matrix alignment in tissues from ambulatory (Amb + IGF) and hindlimb unloaded (HU + IGF) animals; indicating a considerable improvement in the matrix structure in animals treated with IGF-I. Animals that were treated with both GH and IGF-I showed similar improvement to that seen with IGF-I in unloaded tissues (HU + GH + IGF) but showed no improvement in ambulatory tissues (Amb + GH + IGF).

Mentions: Representative H&E stained sections (Fig. 4) revealed hypercellularity and extracellular matrix disorganization in injured tissues from both ambulatory and suspended animals. Ligaments from Sham animals demonstrated the characteristic crimp pattern and aligned fibroblasts associated with normal ligament (Fig. 4). However, while Amb + Sal animals revealed normal scar morphology, tissues from HU + Sal animals had pockets of cell clusters, cellular misalignment, and misaligned collagen bundles oriented in separate directions creating discontinuities and voids within the matrix confirming a previous report [48]. Furthermore, while matrices from animals treated with GH had abnormal cell clusters and no gross improvement in matrix organization in both ambulatory and unloaded tissues, tissues from animals treated with IGF-I showed substantially increased matrix density and collagen alignment (Fig. 4); a morphology also present in tissues from HU + GH + IGF-I animals.


Systemic administration of IGF-I enhances healing in collagenous extracellular matrices: evaluation of loaded and unloaded ligaments.

Provenzano PP, Alejandro-Osorio AL, Grorud KW, Martinez DA, Vailas AC, Grindeland RE, Vanderby R - BMC Physiol. (2007)

Representative tissue sections taken from the midsubstance region of control normal tissue (Sham) and scar tissues (Saline, GH, IGF-I, GH+IGF-I). The longitudinal axis of the ligament is from the top left to bottom right of each image (200X). Tissues from sham control (Sham) animals have the characteristic crimp pattern and aligned fibroblasts associated with normal tissue. Examination of scar tissue from ambulatory healing animals (Amb + Sal) revealed typical scar morphology with matrix disorganization and hypercellularity. In contrast to ambulatory animals, hindlimb unloaded (HU + Sal) animals showed abnormal scar formation with pockets of cell clusters and misaligned collagen fibers creating defects and voids by not connecting. Examination of extracellular matrices from GH treated animals revealed no improvement in matrix organization in tissues from ambulatory (Amb + GH) or hindlimb unloaded (HU + GH) animals. However, animals treated with IGF-I showed extensively increased matrix density and substantially improved matrix alignment in tissues from ambulatory (Amb + IGF) and hindlimb unloaded (HU + IGF) animals; indicating a considerable improvement in the matrix structure in animals treated with IGF-I. Animals that were treated with both GH and IGF-I showed similar improvement to that seen with IGF-I in unloaded tissues (HU + GH + IGF) but showed no improvement in ambulatory tissues (Amb + GH + IGF).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851714&req=5

Figure 4: Representative tissue sections taken from the midsubstance region of control normal tissue (Sham) and scar tissues (Saline, GH, IGF-I, GH+IGF-I). The longitudinal axis of the ligament is from the top left to bottom right of each image (200X). Tissues from sham control (Sham) animals have the characteristic crimp pattern and aligned fibroblasts associated with normal tissue. Examination of scar tissue from ambulatory healing animals (Amb + Sal) revealed typical scar morphology with matrix disorganization and hypercellularity. In contrast to ambulatory animals, hindlimb unloaded (HU + Sal) animals showed abnormal scar formation with pockets of cell clusters and misaligned collagen fibers creating defects and voids by not connecting. Examination of extracellular matrices from GH treated animals revealed no improvement in matrix organization in tissues from ambulatory (Amb + GH) or hindlimb unloaded (HU + GH) animals. However, animals treated with IGF-I showed extensively increased matrix density and substantially improved matrix alignment in tissues from ambulatory (Amb + IGF) and hindlimb unloaded (HU + IGF) animals; indicating a considerable improvement in the matrix structure in animals treated with IGF-I. Animals that were treated with both GH and IGF-I showed similar improvement to that seen with IGF-I in unloaded tissues (HU + GH + IGF) but showed no improvement in ambulatory tissues (Amb + GH + IGF).
Mentions: Representative H&E stained sections (Fig. 4) revealed hypercellularity and extracellular matrix disorganization in injured tissues from both ambulatory and suspended animals. Ligaments from Sham animals demonstrated the characteristic crimp pattern and aligned fibroblasts associated with normal ligament (Fig. 4). However, while Amb + Sal animals revealed normal scar morphology, tissues from HU + Sal animals had pockets of cell clusters, cellular misalignment, and misaligned collagen bundles oriented in separate directions creating discontinuities and voids within the matrix confirming a previous report [48]. Furthermore, while matrices from animals treated with GH had abnormal cell clusters and no gross improvement in matrix organization in both ambulatory and unloaded tissues, tissues from animals treated with IGF-I showed substantially increased matrix density and collagen alignment (Fig. 4); a morphology also present in tissues from HU + GH + IGF-I animals.

Bottom Line: Tissues from ambulatory animals receiving only saline had significantly greater strength than tissue from saline receiving hindlimb unloaded animals.Addition of GH alone did not have a significant effect on either group, while addition of GH+IGF-I significantly improved force, stress, and modulus values in MCLs from hindlimb unloaded animals.Growth hormone alone did not result in any significant improvement contrary to our hypothesis, while GH + IGF-I produced remarkable improvement in hindlimb unloaded animals.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept. of Biomedical Engineering, University of Wisconsin, Madison, WI, USA. ppproven@wisc.edu

ABSTRACT

Background: Insulin-like growth factor-I (IGF-I) plays a crucial role in wound healing and tissue repair. We tested the hypotheses that systemic administration of IGF-I, or growth hormone (GH), or both (GH+IGF-I) would improve healing in collagenous connective tissue, such as ligament. These hypotheses were examined in rats that were allowed unrestricted activity after injury and in animals that were subjected to hindlimb disuse. Male rats were assigned to three groups: ambulatory sham-control, ambulatory-healing, and hindlimb unloaded-healing. Ambulatory and hindlimb unloaded animals underwent surgical disruption of their knee medial collateral ligaments (MCLs), while sham surgeries were performed on control animals. Healing animals subcutaneously received systemic doses of either saline, GH, IGF-I, or GH+IGF-I. After 3 weeks, mechanical properties, cell and matrix morphology, and biochemical composition were examined in control and healing ligaments.

Results: Tissues from ambulatory animals receiving only saline had significantly greater strength than tissue from saline receiving hindlimb unloaded animals. Addition of IGF-I significantly improved maximum force and ultimate stress in tissues from both ambulatory and hindlimb unloaded animals with significant increases in matrix organization and type-I collagen expression. Addition of GH alone did not have a significant effect on either group, while addition of GH+IGF-I significantly improved force, stress, and modulus values in MCLs from hindlimb unloaded animals. Force, stress, and modulus values in tissues from hindlimb unloaded animals receiving IGF-I or GH+IGF-I exceeded (or were equivalent to) values in tissues from ambulatory animals receiving only saline with greatly improved structural organization and significantly increased type-I collagen expression. Furthermore, levels of IGF-receptor were significantly increased in tissues from hindlimb unloaded animals treated with IGF-I.

Conclusion: These results support two of our hypotheses that systemic administration of IGF-I or GH+IGF-I improve healing in collagenous tissue. Systemic administration of IGF-I improves healing in collagenous extracellular matrices from loaded and unloaded tissues. Growth hormone alone did not result in any significant improvement contrary to our hypothesis, while GH + IGF-I produced remarkable improvement in hindlimb unloaded animals.

Show MeSH
Related in: MedlinePlus