转化生长因子-β对肌腱愈合和粘连影响的实验研究
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摘要
第一部分肌腱愈合过程中转化生长因子-β1基因表达的变化
目的了解兔屈趾肌腱Ⅱ区伤口愈合过程中转化生长因子-β1(transforminggrowth factorβ1，TGF-β1)基因表达的变化。
方法60只成年新西兰大白兔左前中趾Ⅱ区屈趾深肌腱被完全切断并修复，分别于1、7、14、21、28、56天获取肌腱，用原位杂交和免疫组化技术分析TGF-β1的表达情况。
结果在无损伤对照组，仅有少量肌腱细胞表达TGF-β1mRNA，其周围的腱鞘成纤维细胞也有低水平的TGF-β1mRNA表达；相比较，损伤修复后的肌腱细胞和腱鞘成纤维细胞的TGF-β1mRNA表达量明显增加。
结论正常无损伤的肌腱和腱鞘细胞能产生TGF-β1，当肌腱损伤后，细胞因子被激活，增加的细胞因子主要由肌腱细胞与腱鞘细胞产生，此结果与肌腱的内、外源性愈合机制是一致的。
第二部分肌腱愈合过程中转化生长因子-β1受体表达的变化
目的了解兔屈趾肌腱Ⅱ区伤口愈合过程中转化生长因子-β1(transforminggrowth factorβ1 Receptors，TGF-βR1)在不同时间和部位的表达情况。
方法42只成年新西兰大白兔左前中趾Ⅱ区屈趾深肌腱被完全切断并修复，分别于1、7、14、21、28、56天获取肌腱(每个时间点6只)，对照组取没有损伤和修复的屈趾肌腱(6只)，用Western blot和免疫组化技术分析TGF-βR1的表达情况。
结果切断修复后的肌腱Western blot和免疫组化染色均发现TGF-βR1蛋白的上调，在实验组，TGF-βR1主要集中在腱鞘、腱外膜和沿肌腱切口处，TGF-βR1的表达水平在14天达到高峰，直到56天才明显降低。对照组，只见极少的受体表达。
结论肌腱损伤修复后，肌腱和腱鞘TGF-βR1的表达明显增加，在术后14天达到高峰，56天开始降低，这种受体上调可能为屈指肌腱术后疤痕形成的生物学调节提供新的途径。
第三部分转化生长因子-β1对肌腱腱鞘、腱外膜和腱内膜细胞增殖和胶原产生的影响
目的探讨兔屈趾肌腱腱鞘、腱外膜和腱内膜细胞增殖、胶原产生和TGF-β_1对细胞的增殖和胶原产生的影响。
方法从兔屈趾肌腱分离腱鞘、腱外膜和腱内膜细胞并培养，测量使用TGF-β_1培养后，细胞的数量和胶原产生量，并与不使用TGF-β_1培养的对照组比较。另外，通过RT-PCR反应测定使用TGF-β_1前后各种细胞Ⅰ型胶原基因的表达。
结果所有三种细胞均可以产生Ⅰ、Ⅱ、Ⅲ型胶原，TGF-β_1使培养的细胞数量降低，但能显著性地增加Ⅰ、Ⅱ、Ⅲ型胶原产生和Ⅰ型胶原基因的表达。
结论调节TGF-β_1的水平能调节胶原的产生，可能为临床上防止肌腱粘连提供新的途径。
第四部分乳酸对肌腱细胞转化生长因子-β表达的调节作用
目的探讨乳酸对兔屈趾肌腱腱鞘、腱外膜和腱内膜细胞TGF-β及其受体产生的影响。
方法从兔屈趾肌腱分离腱鞘、腱外膜和腱内膜细胞并分别进行培养，在使用25mmol／L的乳酸培养后，酶联免疫吸附试验定量检测TGF-β及其受体的表达，同时应用原位杂交技术测量TGF-β1 mRNA的表达。
结果乳酸能显著增加三种细胞所有TGF-β及其受体的表达(P＜0.05)，其中腱鞘细胞的TGF-β1和TGF-β2增加值最大，腱外膜细胞的TGF-β1和TGF-β2的受体增加值最大，腱内膜细胞则为TGF-β3增加值最大；乳酸还显著增加三种细胞的TGF-β1 mRNA表达。
结论乳酸能显著增加肌腱细胞的TGF-β、TGF-β受体和TGF-β1mRNA的表达，因此为肌腱愈合过程中调节TGF-β水平提供新的途径。
第五部分乳酸对肌腱腱鞘、腱外膜和腱内膜细胞增殖和生物学活性的影响
目的探讨兔屈趾肌腱腱鞘、腱外膜和腱内膜细胞增殖、胶原产生和乳酸对细胞的增殖、胶原产生和对TGF-β_1、b-FGF、IL-8分泌的影响。
方法从兔屈趾肌腱分离腱鞘、腱外膜和腱内膜细胞并培养，测量使用乳酸培养后，细胞的数量，胶原产生量和TGF-β_1、b-FGF、IL-8分泌量，并与不使用乳酸培养的对照组比较。
结果所有三种细胞均可以产生Ⅰ、Ⅱ、Ⅲ型胶原，乳酸使培养的细胞数量降低，但能显著性地增加Ⅰ、Ⅱ、Ⅲ型胶原组织产生，TGF-β_1、b-FGF的分泌和减少IL-8的分泌。
结论乳酸能增加腱鞘成纤维细胞、腱外膜细胞和腱内膜细胞的胶原产生量，而这种刺激作用可能与增加TGF-β_1、b-FGF和减少IL-8的分泌量有关，通过对乳酸的调节可能为预防肌腱损伤修复后的粘连提供新的途径。
Part one
Gene Expression of Transforming Growth Factor beta-1 in a Rabbit Zone II Flexor Tendon Wound Healing
Objectives To examine the expression of transforming growth factor beta-1 mRNA in a rabbit zone II flexor tendon wound-healing model.
Methods Forty-eight New Zealand White rabbit forepaws underwent complete transaction and repair of the middle digit flexor digitorum profundus tendon in zone II. Tendons were harvested at increasing time intervals (1, 7, 14, 21, 28, and 56day) and analyzed by in situ hybridization and immunohistochemistry to determine the expression patterns of transforming growth factor beta-1.
Results A small number of tenocytes exhibited expression of transforming growth factor beta-1 mRNA in nonwounded control tendon specimens. The surrounding tendon sheath in these control specimens also revealed low numbers of fibroblasts expressing transforming growth factor beta-1 mRNA. In contrast, flexor tendons subjected to transaction and repair exhibited increased signal for transforming growth factor beta-1 mRNA in both resident tenocytes and fibroblasts from the tendon sheath.
Conclusions The normal unwounded tenocytes and tendon sheath cells are capable of transforming growth factor beta-1 production. The cytokine is activated in the tendon wound environment. The upregulation of this cytokine in both tenocytes and tendon sheath fibroblasts are coincidence with both extrinsic and intrinsic mechanisms for tendon repair.
Part two
Expression of Transforming Growth Factor beta-1 Receptors in a Rabbit Zone II Flexor Tendon Wound Healing
Objectives TO analyzed the temporal and spatial distribution of TGF-[beta] receptor RI in a rabbit zone II flexor tendon wound healing model.
Methods Forty-two adult New Zealand White rabbit forepaws underwent isolation of the middle digit flexor digitorum profundus tendon in zone II. The tendons underwent transection in zone II and immediate repair. The tendons were harvested at increasing time points: 1, 7, 14, 21,28, and 56 days postoperatively (n = 6 at each time point). The control flexor tendons were harvested without transection and repair (n = 6). Western blot and Immunohistochemical analysis was used to detect the expression patterns for TGF-[beta] receptors RI.
Results Western blot and Immunohistochemical staining of the transected and repaired tendons demonstrated up-regulation of TGF-beta RI protein levels. TGF-beta receptor production in the experimental group (transection and repair) was concentrated in the tendon sheath, the epitenon and along the repair site. Furthermore, the TGF-beta receptor expression levels peaked at day 14 and decreased by day 56 postoperatively. In contrast, minimal receptor expression was observed in the untransected and unrepaired control tendons.
Conclusions The tendon sheath and epitenon have the highest TGF-beta receptor expression after injury and repair; The peak levels of TGF-[beta] receptor expression occurred at day 14 and decreased by day 56 after wounding and repair; Understanding the up-regulation of TGF-[beta] isoforms and the up-regulation of their corresponding receptors during flexor tendon wound healing provides new targets for biomolecular modulation of postoperative scar formation.
Part three
Effects of TGF-β1 on proliferation and collagen production of tendon sheath fibroblasts, epitenon tenocytes, and endotenon tenocytes
Objective To study proliferation and collagen production of tendon sheath fibroblasts, epitenon tenocytes, and endotenon tenocytes; and effects of TGF-β_1 on cell proliferation and collagen production by each of these 3 cell types in rabbit flexor tendon.
Methods Three cell lines: tendon sheath, epitenon, and endotenon were isolated from rabbit flexor tendon and cultured. Cell culture media was supplemented with 5ng/ml of TGF-β_1. Cell number and collagen I, II and III production were measured and compared with unsupplemented control culture. Expression of type I collagen was determined by quantitative analysis of products of reverse-transcription polymerase chain reaction.
Results All 3 cell lines produced collagen I, II and III. The addition of TGF-β_1 to cell media resulted in a decrease in cell number in all 3 cell1 lines that did not reach statistical significance. There was a significant increase (p<0. 05) in collagen I, II and III production and expression levels of type I collagen with the addition of
Conclusions Modulation of TGF-β_1 levels may provide a means to modulate collagen production in tendon and may provide a mechanism to modulate adhesion formation clinically.
Part four
Effects of lactate on TGF-β expression of flxor tendon cells
Objective To study the effects of lactate on TGF-β peptide and receptor production by flexor tendon cells.
Methods Tendon sheath fibroblasts, epitennon tenocytes, and endotendonon tenocytes were isolated from rabbit flexor tendon and cultured separately. Cell cultures were supplemented with lactate and the expression of three TGF-β peptide isoforms(β1, β2, and β3) and three receptor isoforms(R1, R2, andR3) was quantified with enzyme-linked immunosorbent assay. The expression of TGF-β1 mRNA was also assessed with in situ hybridization and image analysis.
Results Supplementation of the cell culture medium with lactate significantly (P<0.05) increased the expression of all TGF-β peptide and receptor isoforms in all three cell lines. Tendon sheath fibroblasts exhibited the greatest increases in β1 and β2 peptide isoform expression, Whereas epitenon tenocytes exhibited the greatest increases in receptor isoform R1 and R2 expression, endotenon tenocytes demionstrated the greatest increase in β3 peptide expression. All three tendon cell types demonstrated significant (P<0.05) increases in TGF-β1 mRNA expression when exposed to lactate.
Conclusion Lactate significantly increased the expression of TGF-β peptide、TGF-β receptor and TGF-β1 mRNA. Modulation of lactate levels may provide a means of modulating the effecs of TGF-β on adhesion formation in flexor tendon wound healing.
Part five
Effects of lactate on proliferation and biological activities of tendon sheath fibroblasts, epitenon tenocytes, and endotenon tenocytes
Objective To study proliferation and collagen production of tendon sheath fibroblasts, epitenon tenocytes, and endotenon tenocytes; and effects of lactate on cell proliferation, collagen production and secretion of TGF-β_1, b-FGF, and IL-8 by each of these 3 cell types in rabbit flexor tendon.
Methods Three cell lines: tendon sheath, epitenon, and endotenon were isolated from rabbit flexor tendon and cultured. Cell culture media was supplemented with 25mml/L of lactate. Cell number, collagen I , II and III production, and secretion of TGF-β_1, b-FGF, and IL-8 were measured and compared with unsupplemented control culture.
Results All 3 cell lines produced collagen I, II and III. The addition of lactate to cell media resulted in a decrease in cell number in all 3 cell lines that did not reach statistical significance. There was a significant increase (p<0.05) in collagen I, II and III production and secretion of TGF- β_1, b-FGF,and IL-8.
Conclusions Modulation of lactate levels may provide a means to modulate collagen production in tendon and may provide a mechanism to modulate adhesion formation clinically.
目的了解兔屈趾肌腱Ⅱ区伤口愈合过程中转化生长因子-β1(transforminggrowth factorβ1，TGF-β1)基因表达的变化。
方法60只成年新西兰大白兔左前中趾Ⅱ区屈趾深肌腱被完全切断并修复，分别于1、7、14、21、28、56天获取肌腱，用原位杂交和免疫组化技术分析TGF-β1的表达情况。
结果在无损伤对照组，仅有少量肌腱细胞表达TGF-β1mRNA，其周围的腱鞘成纤维细胞也有低水平的TGF-β1mRNA表达；相比较，损伤修复后的肌腱细胞和腱鞘成纤维细胞的TGF-β1mRNA表达量明显增加。
结论正常无损伤的肌腱和腱鞘细胞能产生TGF-β1，当肌腱损伤后，细胞因子被激活，增加的细胞因子主要由肌腱细胞与腱鞘细胞产生，此结果与肌腱的内、外源性愈合机制是一致的。
第二部分肌腱愈合过程中转化生长因子-β1受体表达的变化
目的了解兔屈趾肌腱Ⅱ区伤口愈合过程中转化生长因子-β1(transforminggrowth factorβ1 Receptors，TGF-βR1)在不同时间和部位的表达情况。
方法42只成年新西兰大白兔左前中趾Ⅱ区屈趾深肌腱被完全切断并修复，分别于1、7、14、21、28、56天获取肌腱(每个时间点6只)，对照组取没有损伤和修复的屈趾肌腱(6只)，用Western blot和免疫组化技术分析TGF-βR1的表达情况。
结果切断修复后的肌腱Western blot和免疫组化染色均发现TGF-βR1蛋白的上调，在实验组，TGF-βR1主要集中在腱鞘、腱外膜和沿肌腱切口处，TGF-βR1的表达水平在14天达到高峰，直到56天才明显降低。对照组，只见极少的受体表达。
结论肌腱损伤修复后，肌腱和腱鞘TGF-βR1的表达明显增加，在术后14天达到高峰，56天开始降低，这种受体上调可能为屈指肌腱术后疤痕形成的生物学调节提供新的途径。
第三部分转化生长因子-β1对肌腱腱鞘、腱外膜和腱内膜细胞增殖和胶原产生的影响
目的探讨兔屈趾肌腱腱鞘、腱外膜和腱内膜细胞增殖、胶原产生和TGF-β_1对细胞的增殖和胶原产生的影响。
方法从兔屈趾肌腱分离腱鞘、腱外膜和腱内膜细胞并培养，测量使用TGF-β_1培养后，细胞的数量和胶原产生量，并与不使用TGF-β_1培养的对照组比较。另外，通过RT-PCR反应测定使用TGF-β_1前后各种细胞Ⅰ型胶原基因的表达。
结果所有三种细胞均可以产生Ⅰ、Ⅱ、Ⅲ型胶原，TGF-β_1使培养的细胞数量降低，但能显著性地增加Ⅰ、Ⅱ、Ⅲ型胶原产生和Ⅰ型胶原基因的表达。
结论调节TGF-β_1的水平能调节胶原的产生，可能为临床上防止肌腱粘连提供新的途径。
第四部分乳酸对肌腱细胞转化生长因子-β表达的调节作用
目的探讨乳酸对兔屈趾肌腱腱鞘、腱外膜和腱内膜细胞TGF-β及其受体产生的影响。
方法从兔屈趾肌腱分离腱鞘、腱外膜和腱内膜细胞并分别进行培养，在使用25mmol／L的乳酸培养后，酶联免疫吸附试验定量检测TGF-β及其受体的表达，同时应用原位杂交技术测量TGF-β1 mRNA的表达。
结果乳酸能显著增加三种细胞所有TGF-β及其受体的表达(P＜0.05)，其中腱鞘细胞的TGF-β1和TGF-β2增加值最大，腱外膜细胞的TGF-β1和TGF-β2的受体增加值最大，腱内膜细胞则为TGF-β3增加值最大；乳酸还显著增加三种细胞的TGF-β1 mRNA表达。
结论乳酸能显著增加肌腱细胞的TGF-β、TGF-β受体和TGF-β1mRNA的表达，因此为肌腱愈合过程中调节TGF-β水平提供新的途径。
第五部分乳酸对肌腱腱鞘、腱外膜和腱内膜细胞增殖和生物学活性的影响
目的探讨兔屈趾肌腱腱鞘、腱外膜和腱内膜细胞增殖、胶原产生和乳酸对细胞的增殖、胶原产生和对TGF-β_1、b-FGF、IL-8分泌的影响。
方法从兔屈趾肌腱分离腱鞘、腱外膜和腱内膜细胞并培养，测量使用乳酸培养后，细胞的数量，胶原产生量和TGF-β_1、b-FGF、IL-8分泌量，并与不使用乳酸培养的对照组比较。
结果所有三种细胞均可以产生Ⅰ、Ⅱ、Ⅲ型胶原，乳酸使培养的细胞数量降低，但能显著性地增加Ⅰ、Ⅱ、Ⅲ型胶原组织产生，TGF-β_1、b-FGF的分泌和减少IL-8的分泌。
结论乳酸能增加腱鞘成纤维细胞、腱外膜细胞和腱内膜细胞的胶原产生量，而这种刺激作用可能与增加TGF-β_1、b-FGF和减少IL-8的分泌量有关，通过对乳酸的调节可能为预防肌腱损伤修复后的粘连提供新的途径。
Part one
Gene Expression of Transforming Growth Factor beta-1 in a Rabbit Zone II Flexor Tendon Wound Healing
Objectives To examine the expression of transforming growth factor beta-1 mRNA in a rabbit zone II flexor tendon wound-healing model.
Methods Forty-eight New Zealand White rabbit forepaws underwent complete transaction and repair of the middle digit flexor digitorum profundus tendon in zone II. Tendons were harvested at increasing time intervals (1, 7, 14, 21, 28, and 56day) and analyzed by in situ hybridization and immunohistochemistry to determine the expression patterns of transforming growth factor beta-1.
Results A small number of tenocytes exhibited expression of transforming growth factor beta-1 mRNA in nonwounded control tendon specimens. The surrounding tendon sheath in these control specimens also revealed low numbers of fibroblasts expressing transforming growth factor beta-1 mRNA. In contrast, flexor tendons subjected to transaction and repair exhibited increased signal for transforming growth factor beta-1 mRNA in both resident tenocytes and fibroblasts from the tendon sheath.
Conclusions The normal unwounded tenocytes and tendon sheath cells are capable of transforming growth factor beta-1 production. The cytokine is activated in the tendon wound environment. The upregulation of this cytokine in both tenocytes and tendon sheath fibroblasts are coincidence with both extrinsic and intrinsic mechanisms for tendon repair.
Part two
Expression of Transforming Growth Factor beta-1 Receptors in a Rabbit Zone II Flexor Tendon Wound Healing
Objectives TO analyzed the temporal and spatial distribution of TGF-[beta] receptor RI in a rabbit zone II flexor tendon wound healing model.
Methods Forty-two adult New Zealand White rabbit forepaws underwent isolation of the middle digit flexor digitorum profundus tendon in zone II. The tendons underwent transection in zone II and immediate repair. The tendons were harvested at increasing time points: 1, 7, 14, 21,28, and 56 days postoperatively (n = 6 at each time point). The control flexor tendons were harvested without transection and repair (n = 6). Western blot and Immunohistochemical analysis was used to detect the expression patterns for TGF-[beta] receptors RI.
Results Western blot and Immunohistochemical staining of the transected and repaired tendons demonstrated up-regulation of TGF-beta RI protein levels. TGF-beta receptor production in the experimental group (transection and repair) was concentrated in the tendon sheath, the epitenon and along the repair site. Furthermore, the TGF-beta receptor expression levels peaked at day 14 and decreased by day 56 postoperatively. In contrast, minimal receptor expression was observed in the untransected and unrepaired control tendons.
Conclusions The tendon sheath and epitenon have the highest TGF-beta receptor expression after injury and repair; The peak levels of TGF-[beta] receptor expression occurred at day 14 and decreased by day 56 after wounding and repair; Understanding the up-regulation of TGF-[beta] isoforms and the up-regulation of their corresponding receptors during flexor tendon wound healing provides new targets for biomolecular modulation of postoperative scar formation.
Part three
Effects of TGF-β1 on proliferation and collagen production of tendon sheath fibroblasts, epitenon tenocytes, and endotenon tenocytes
Objective To study proliferation and collagen production of tendon sheath fibroblasts, epitenon tenocytes, and endotenon tenocytes; and effects of TGF-β_1 on cell proliferation and collagen production by each of these 3 cell types in rabbit flexor tendon.
Methods Three cell lines: tendon sheath, epitenon, and endotenon were isolated from rabbit flexor tendon and cultured. Cell culture media was supplemented with 5ng/ml of TGF-β_1. Cell number and collagen I, II and III production were measured and compared with unsupplemented control culture. Expression of type I collagen was determined by quantitative analysis of products of reverse-transcription polymerase chain reaction.
Results All 3 cell lines produced collagen I, II and III. The addition of TGF-β_1 to cell media resulted in a decrease in cell number in all 3 cell1 lines that did not reach statistical significance. There was a significant increase (p<0. 05) in collagen I, II and III production and expression levels of type I collagen with the addition of
Conclusions Modulation of TGF-β_1 levels may provide a means to modulate collagen production in tendon and may provide a mechanism to modulate adhesion formation clinically.
Part four
Effects of lactate on TGF-β expression of flxor tendon cells
Objective To study the effects of lactate on TGF-β peptide and receptor production by flexor tendon cells.
Methods Tendon sheath fibroblasts, epitennon tenocytes, and endotendonon tenocytes were isolated from rabbit flexor tendon and cultured separately. Cell cultures were supplemented with lactate and the expression of three TGF-β peptide isoforms(β1, β2, and β3) and three receptor isoforms(R1, R2, andR3) was quantified with enzyme-linked immunosorbent assay. The expression of TGF-β1 mRNA was also assessed with in situ hybridization and image analysis.
Results Supplementation of the cell culture medium with lactate significantly (P<0.05) increased the expression of all TGF-β peptide and receptor isoforms in all three cell lines. Tendon sheath fibroblasts exhibited the greatest increases in β1 and β2 peptide isoform expression, Whereas epitenon tenocytes exhibited the greatest increases in receptor isoform R1 and R2 expression, endotenon tenocytes demionstrated the greatest increase in β3 peptide expression. All three tendon cell types demonstrated significant (P<0.05) increases in TGF-β1 mRNA expression when exposed to lactate.
Conclusion Lactate significantly increased the expression of TGF-β peptide、TGF-β receptor and TGF-β1 mRNA. Modulation of lactate levels may provide a means of modulating the effecs of TGF-β on adhesion formation in flexor tendon wound healing.
Part five
Effects of lactate on proliferation and biological activities of tendon sheath fibroblasts, epitenon tenocytes, and endotenon tenocytes
Objective To study proliferation and collagen production of tendon sheath fibroblasts, epitenon tenocytes, and endotenon tenocytes; and effects of lactate on cell proliferation, collagen production and secretion of TGF-β_1, b-FGF, and IL-8 by each of these 3 cell types in rabbit flexor tendon.
Methods Three cell lines: tendon sheath, epitenon, and endotenon were isolated from rabbit flexor tendon and cultured. Cell culture media was supplemented with 25mml/L of lactate. Cell number, collagen I , II and III production, and secretion of TGF-β_1, b-FGF, and IL-8 were measured and compared with unsupplemented control culture.
Results All 3 cell lines produced collagen I, II and III. The addition of lactate to cell media resulted in a decrease in cell number in all 3 cell lines that did not reach statistical significance. There was a significant increase (p<0.05) in collagen I, II and III production and secretion of TGF- β_1, b-FGF,and IL-8.
Conclusions Modulation of lactate levels may provide a means to modulate collagen production in tendon and may provide a mechanism to modulate adhesion formation clinically.
引文
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