Influence of Decorin and Biglycan on Mechanical Properties of Multiple Tendons in Knockout Mice

Sakurai

et al. 2008

Arthritis & Rheumatism

Objective. To evaluate histologic, immunohistochemical, and molecular changes in tendon induced by altered strain in a large-animal model.Methods. A full-thickness partial-width laceration of the infraspinatus tendon was created in 5 sheep, while 5 sham-operated sheep were used as controls. Sheep were killed after 4 weeks, and 4 differentially stressed tendon regions (tensile or near bone attachment from overstressed or stress-deprived halves) were evaluated for histopathology, proteoglycan (PG) accumulation, and characterization of glycosaminoglycans and aggrecan catabolites. Gene expression of matrix components, enzymes, and inhibitors was analyzed by reverse transcriptase-polymerase chain reaction.Results. Histopathologic changes were detected in both overstressed and stress-deprived tensile tendon, but only in stress-deprived tendon near bone. In overstressed and stress-deprived tensile tendon, levels of keratan sulfate, chondroitin 4-sulfate, and chondroitin 6-sulfate were increased. In overstressed tensile tendon, levels of ADAMTS-generated aggrecan catabolites were increased. There was increased matrix metalloproteinase 13 (MMP-13) and decreased fibromodulin and decorin expression in all regions. Increased MMP-1, MMP-9, MMP-14, and ADAMTS-1 expression, and decreased type II collagen expression were restricted to stress-deprived tendon. In stress-deprived boneattachment regions, messenger RNA (mRNA) for aggrecan was decreased, and ADAMTS was increased. In overstressed tensile tendon, aggrecan mRNA was increased, and ADAMTS was decreased.Conclusion. The distinct molecular changes in adjacent tissue implicate altered strain rather than humoral factors in controlling abnormal tenocyte metabolism, and highlight the importance of regional sampling. Tendon abnormalities induced by increased strain are accompanied by increased aggrecan, decreased ADAMTS, and low PG expression, which may negatively impact the structural integrity of the tissue and predispose to rupture.Injuries of the shoulder due to overuse are increasingly prevalent in both the sporting arena and the workplace. Occupational injury of the shoulder is second only to neck and low back pain in the frequency of consultation by general practitioners, with the most common injury involving the rotator cuff. (1,2) The prevalence of rotator cuff conditions increases with age, from 30-50% in the seventh decade of life to a staggering 70-80% by the ninth (3,4). Although most cases are treated conservatively, many patients undergo surgical repair with a prolonged convalescence. There are no drugs to specifically treat disorders of the rotator cuff or other tendons, and many surgical repairs fail within 12 months (5). Lack of knowledge of the fundamental mechanisms that underlie tendon breakdown results in limited and inadequate management options for tendon disorders.

Section: Discussionmentioning

confidence: 99%

Modulation of aggrecan and ADAMTS expression in ovine tendinopathy induced by altered strain

Sakurai

et al. 2008

Arthritis & Rheumatism

“…Thus, it was believed that absence of decorin would lead to weaker tissues and that the opposite trend could be expected if decorin is overexpressed. However, either superior or similar material parameters have recently been reported for tendons from decorin deficient adult [37] and postnatal mice [34] as well as decorin deficient engineered gels [16], compared to wild-type controls. In addition, greater than normal decorin expression has been reported in prolapsed mitral valve [38] in which the tissue is weakened [39], and our lab has histochemically demonstrated that excess decorin is present valves that were exposed to altered shear stress [40].…”

Section: Discussionmentioning

confidence: 99%

Influence of cyclic strain and decorin deficiency on 3D cellularized collagen matrices

et al. 2008

Self Cite

Cyclic strain evokes the expression of the small leucine-rich proteoglycans decorin and biglycan in 2-D cultures and native tissues. However, strain dependent expression of these proteoglycans has not been demonstrated in engineered tissues. We hypothesized that the absence of decorin may compromise the effect of cyclic strain on the development of engineered tissues. Thus, we investigated the contribution of decorin to tissue organization in cyclically-strained collagen gels relative to statically-cultured controls. Decorin null (Dcn −/− ) and wild-type murine embryonic fibroblasts were seeded within collagen gels and mechanically conditioned using a Flexcell ® Tissue Train ® culture system. After eight days, the cyclically-strained samples demonstrated greater collagen fibril density, proteoglycan content, and material strength for both cell types. On the other hand, increases in cell density, collagen fibril diameter, and biglycan expression were observed only in the cyclically-strained gels seeded with Dcn −/− cells. Although cyclic strain caused an elevation in proteoglycan expression regardless of cell type, the type of proteoglycan differed between groups: the Dcn −/− cell-seeded gels produced an excess of biglycan not found in the wild-type controls. These results suggest that decorin-mediated tissue organization is strongly dependent upon tissue type and mechanical environment.

Journal Orthopaedic Research

“…Various investigators have assessed the contributions of selected matrix components (e.g., cytokines, proteoglycans) to tendon structure, composition, and mechanical properties using transgenic and knockout mice. [14][15][16][17][18][19][20][21][22] Despite the importance of these findings, the alteration or removal of matrix proteins may result in an abnormal or pathologic tissue phenotype due to biological compensation. 16 Therefore, these animal models may be inappropriate for studying the genetic regulation of normal tendon and ligament properties.…”

Section: Introductionmentioning

confidence: 99%

Variability in tendon and knee joint biomechanics among inbred mouse strains

Wang

Banack

Tsai

et al. 2006

Hereditary factors are thought to be responsible for impaired tendon function and joint laxity. The present study investigated the genotypic variability of knee laxity and stiffness and tendon mechanical and geometric properties among 16-week-old female A/J, C57BL/6J (B6), and C3H/HeJ (C3H) inbred mice. In one group of mice, knee mechanics were quantified using a custom loading apparatus enabling translation of the tibia against a stationary femur. In a second group, flexor digitorum longus and Achilles tendons from the left hind limb underwent biomechanical testing, while those of the contralateral limb were analyzed histologically for determination of crosssectional area. Our results demonstrate that tendon and joint mechanics varied significantly among the inbred mouse strains, indicating that biomechanical properties are genetically determined. A/J mouse knees exhibited greater laxity (p < 0.001) and lower stiffness (p < 0.001) compared to those of the B6 and C3H mice. The genotypic differences in whole joint properties were similar to those of the tendons' structural biomechanical traits. Although body mass did not differ (p > 0.2) among the three strains, significant genotypic differences were found at the whole tendon, material quality, and morphological levels of the tissue hierarchy. Furthermore, genetic regulation of tendon mechanical properties varied with anatomic site. Patterns of genotypic differences in tendon size were not consistent with those of biomechanical properties, suggesting that unique combinations of structural and compositional factors contribute to tendon growth, adaptation, and development. Therefore, the three inbred strains constitute a useful experimental model to elucidate genetic control of structure-function relationships in normal and healing tendons and ligaments.