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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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Elastic modulus values at 3 weeks (mean ± S.E.M.). The additional of IGF-I significantly improved elastic modulus levels in tissues from ambulatory healing animals when compared to tissues from ambulatory healing animals which received saline (p = 0.049). A significant increase in elastic modulus was present in tissues from hindlimb unloaded animals after the addition of IGF-I or GH+IGF-I when compared to hindlimb unloaded animals receiving saline (p = 0.049 and p = 0.014, respectively). a significantly different from Sham group; b significantly different from Amb + Sal group; c significantly different from HU + Sal group.
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Figure 3: Elastic modulus values at 3 weeks (mean ± S.E.M.). The additional of IGF-I significantly improved elastic modulus levels in tissues from ambulatory healing animals when compared to tissues from ambulatory healing animals which received saline (p = 0.049). A significant increase in elastic modulus was present in tissues from hindlimb unloaded animals after the addition of IGF-I or GH+IGF-I when compared to hindlimb unloaded animals receiving saline (p = 0.049 and p = 0.014, respectively). a significantly different from Sham group; b significantly different from Amb + Sal group; c significantly different from HU + Sal group.

Mentions: Substantial differences in tissue mechanical properties were present between groups. Hindlimb unloading adversely affected ligament healing while IGF-I or GH+IGF-I had a substantial effect on ligament healing in either ambulatory or hindlimb unloaded animals. Maximum force (Fig. 1) was significantly different between tissues from Sham and both Amb + Sal and HU + Sal groups (p = 0.0001 and p = 0.0001, respectively). Hindlimb unloaded animals had significantly decreased maximum force in the MCLs when compared to ambulatory healing animals (Amb + Sal; p = 0.03). In ambulatory animals the addition of IGF-I significantly improved maximum force values by approximately 60% when compared to ambulatory healing animals that received saline (p = 0.0002). Addition of IGF-I and GH+IGF-I in hindlimb unloaded animals significantly increased maximum force values (60% and 74%, respectively) when compared to HU + Sal animals (p = 0.0074 and p = 0.0013, respectively). In fact, addition of IGF-I or GH+IGF-I to hindlimb unloaded animals increased force to be comparable with Amb + Sal animals. Growth hormone alone did not have a significant effect within either the ambulatory or unloaded groups. However, in the unloaded group, GH increased maximum force and brought it closer to values in the Amb + Sal group, yet this increase was not statistically significant (p = 0.16). Ultimate stress (Fig. 2) was significantly decreased in tissues from both ambulatory healing and hindlimb unloaded healing animals when compared to sham control tissues (p = 0.0001 and p = 0.0001, respectively). Ligaments from HU + Sal animals had ultimate stress values that were significantly lower than saline receiving ambulatory animals (p = 0.022). Addition of only IGF-I to ambulatory animals significantly increased ultimate stress when compared to Amb + Sal animals (p = 0.0077). Delivery of IGF-I and GH+IGF-I significantly increased ultimate stress in tissues from the hindlimb unloaded animals when compared to hindlimb unloaded (plus saline) animals (p = 0.0236 and p = 0.0202, respectively). In fact, ultimate stress values after the addition of IGF-I or GH+IGF-I to hindlimb unloaded animals was comparable to ultimate stress values in ambulatory animals receiving saline. In ambulatory animals, no statistically significant effect on ultimate stress values were seen after GH or GH+IGF-I was administered. No significant differences in strain at failure were present between groups. Elastic modulus (Fig. 3) was statistically different between IGF-I and saline treated ambulatory healing animals. Addition of IGF-I in ambulatory animals resulted in an elastic modulus that had an ~49% greater mean value (p = 0.049). In hindlimb unloaded animals the addition of IGF-I or GH+IGF-I resulted in a significant increase in modulus when compared to unloaded animals receiving saline (p = 0.049 and p = 0.014, respectively). Growth hormone alone had no significant effect on elastic modulus in either group.


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)

Elastic modulus values at 3 weeks (mean ± S.E.M.). The additional of IGF-I significantly improved elastic modulus levels in tissues from ambulatory healing animals when compared to tissues from ambulatory healing animals which received saline (p = 0.049). A significant increase in elastic modulus was present in tissues from hindlimb unloaded animals after the addition of IGF-I or GH+IGF-I when compared to hindlimb unloaded animals receiving saline (p = 0.049 and p = 0.014, respectively). a significantly different from Sham group; b significantly different from Amb + Sal group; c significantly different from HU + Sal group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Elastic modulus values at 3 weeks (mean ± S.E.M.). The additional of IGF-I significantly improved elastic modulus levels in tissues from ambulatory healing animals when compared to tissues from ambulatory healing animals which received saline (p = 0.049). A significant increase in elastic modulus was present in tissues from hindlimb unloaded animals after the addition of IGF-I or GH+IGF-I when compared to hindlimb unloaded animals receiving saline (p = 0.049 and p = 0.014, respectively). a significantly different from Sham group; b significantly different from Amb + Sal group; c significantly different from HU + Sal group.
Mentions: Substantial differences in tissue mechanical properties were present between groups. Hindlimb unloading adversely affected ligament healing while IGF-I or GH+IGF-I had a substantial effect on ligament healing in either ambulatory or hindlimb unloaded animals. Maximum force (Fig. 1) was significantly different between tissues from Sham and both Amb + Sal and HU + Sal groups (p = 0.0001 and p = 0.0001, respectively). Hindlimb unloaded animals had significantly decreased maximum force in the MCLs when compared to ambulatory healing animals (Amb + Sal; p = 0.03). In ambulatory animals the addition of IGF-I significantly improved maximum force values by approximately 60% when compared to ambulatory healing animals that received saline (p = 0.0002). Addition of IGF-I and GH+IGF-I in hindlimb unloaded animals significantly increased maximum force values (60% and 74%, respectively) when compared to HU + Sal animals (p = 0.0074 and p = 0.0013, respectively). In fact, addition of IGF-I or GH+IGF-I to hindlimb unloaded animals increased force to be comparable with Amb + Sal animals. Growth hormone alone did not have a significant effect within either the ambulatory or unloaded groups. However, in the unloaded group, GH increased maximum force and brought it closer to values in the Amb + Sal group, yet this increase was not statistically significant (p = 0.16). Ultimate stress (Fig. 2) was significantly decreased in tissues from both ambulatory healing and hindlimb unloaded healing animals when compared to sham control tissues (p = 0.0001 and p = 0.0001, respectively). Ligaments from HU + Sal animals had ultimate stress values that were significantly lower than saline receiving ambulatory animals (p = 0.022). Addition of only IGF-I to ambulatory animals significantly increased ultimate stress when compared to Amb + Sal animals (p = 0.0077). Delivery of IGF-I and GH+IGF-I significantly increased ultimate stress in tissues from the hindlimb unloaded animals when compared to hindlimb unloaded (plus saline) animals (p = 0.0236 and p = 0.0202, respectively). In fact, ultimate stress values after the addition of IGF-I or GH+IGF-I to hindlimb unloaded animals was comparable to ultimate stress values in ambulatory animals receiving saline. In ambulatory animals, no statistically significant effect on ultimate stress values were seen after GH or GH+IGF-I was administered. No significant differences in strain at failure were present between groups. Elastic modulus (Fig. 3) was statistically different between IGF-I and saline treated ambulatory healing animals. Addition of IGF-I in ambulatory animals resulted in an elastic modulus that had an ~49% greater mean value (p = 0.049). In hindlimb unloaded animals the addition of IGF-I or GH+IGF-I resulted in a significant increase in modulus when compared to unloaded animals receiving saline (p = 0.049 and p = 0.014, respectively). Growth hormone alone had no significant effect on elastic modulus in either group.

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