Morphogenesis of Degenerative Changes Predisposing Dogs to Rupture of the Cranial Cruciate Ligament.

IntroductionAnterior cruciate ligament (ACL) degeneration is observed in most osteoarthritis (OA)-affected knee joints. However, the specific spatial and temporal relations of these changes and their association with extracellular matrix (ECM) degeneration are not well understood. The objective of this study was to characterize the patterns and relations of aging-related and OA-associated changes in ACL cells and the ECM.MethodsHuman knee joints from 80 donors (age 23 through 94) were obtained at autopsy. ACL degeneration was assessed histologically by using a quantitative scoring system. Tissue sections were analyzed for cell density, cell organization, ECM components, ECM-degrading enzymes and markers of differentiation, proliferation, and stem cells.ResultsTotal cell number in normal ACL decreased with aging but increased in degenerated ACL, because of the formation of perivascular cell aggregates and islands of chondrocyte-like cells. Matrix metalloproteinase (MMP)-1, -3, and -13 expression was reduced in aging ACL but increased in degenerated ACL, mainly in the chondrocyte-like cells. Collagen I was expressed throughout normal and degenerated ACL. Collagen II and X were detected only in the areas with chondroid metaplasia, which also expressed collagen III. Sox9, Runt-related transcription factor 2 (Runx2), and scleraxis expression was increased in the chondrocyte-like cells in degenerated ACL. Alpha-smooth muscle actin (α-SMA), a marker of myofibroblasts and the progenitor cell marker STRO-1, decreased with aging in normal ACL. In degenerated ACL, the new cell aggregates were positive for α-SMA and STRO-1.ConclusionsACL aging is characterized by reduced cell density and activation. In contrast, ACL degeneration is associated with cell recruitment or proliferation, including progenitor cells or myofibroblasts. Abnormally differentiated chondrocyte-like cell aggregates in degenerated ACL produce abnormal ECM and may predispose to mechanical failure.

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“…Ki-67 is a cell-proliferation marker [5]. In normal ACLs, 27.2% ± 4.1% of ligament cells were Ki-67 positive.…”

Section: Resultsmentioning

confidence: 99%

“…Changes of ACL cell activation and differentiation status have also been documented. Chondroid metaplasia is a feature of degenerated ACL [2,5-7] and may precede and predispose to structural failure [3,8]. …”

Section: Introductionmentioning

confidence: 99%

Cellular and extracellular matrix changes in anterior cruciate ligaments during human knee aging and osteoarthritis

et al. 2013

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“…While acute ligament injury may occur because of a single event overload from trauma, the majority of dogs rupture their CrCL during normal daily activities due to secondary progressive and irreversible degenerative changes within the ligament itself (Zahm, 1965;Pond and Campbell, 1972;Arnoczky and Marshall, 1981;Moore and Read, 1996;Narama et al, 1996). This form of nontraumatic rupture is clinically termed spontaneous CrCL rupture.…”

Section: Introductionmentioning

confidence: 99%

Immunopathological mechanisms in dogs with rupture of the cranial cruciate ligament

Doom

Bruin

Rooster

et al. 2008

Veterinary Immunology and Immunopathology

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The majority of studies on cranial cruciate ligament (CrCL) disease to date have been carried out on dogs that already sustained a CrCL rupture, which is the end-stage of the disease. Investigations have recently been carried out to study humoral and cellular immunopathological mechanisms in predisposed dogs before clinical rupture of the contralateral CrCL. The cruciate ligaments are mainly composed of collagen type I, and immune responses to collagen have been suggested as a cause of CrCL degradation in dogs. None of these investigations showed evidence that anticollagen type I antibodies alone initiate CrCL damage. However, in predisposed dogs a distinct anticollagen type I antibody gradient was found towards the contralateral stifle joint that eventually sustained a CrCL rupture, suggesting that there was an inflammatory process present in these joints before detectable joint instability occurred. The importance of cellular reactivity to collagen type I in cruciate disease also remains unclear. Peripheral blood mononuclear cell proliferation to collagen type I was very diverse in dogs with cruciate disease whereas some sham operated dogs and healthy dogs tested positive as well. It is not yet determined whether cellular reactivity to collagen type I exists locally in the stifle joints nor whether this could initiate CrCL degradation.Inflammatory processes within the stifle joint can alter the composition of the cruciate ligaments. In animal models of immunemediated synovitis, the mechanical strength of the CrCL is significantly reduced. Immunohistochemical studies on synovial tissues from dogs with rheumatoid arthritis and dogs with cruciate disease revealed that the pathologic features are similar in both joint pathologies and that the differences are mainly quantitative. Joint inflammation induced by biochemical factors such as cytokines has been implied in CrCL degeneration. In several studies, the levels of pro-inflammatory and T helper cytokines were measured in dogs that sustained a CrCL rupture, but the exact role of the various cytokines in the pathogenesis of CrCL disease remains inconclusive. More recently, the levels of the cytokines have been investigated over time in predisposed dogs before and after CrCL rupture. IL-8 expression tended to be higher in stifle joints that will rupture their CrCL during the next 6 months than in those that will not, indicating an inflammatory process in these joints before clinical rupture.

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“…In addition, the fibrocytes without nuclei was frequently observed in older dogs, both male and female, compared to the younger ones. This is similar to loss of nuclei in fibrocytes, which is an histopathological characteristic of a ruptured anterior cruciate ligament; therefore, older dogs might more likely be affected than younger dogs [17,18].…”

Section: Discussionmentioning

confidence: 95%

“…And, the entire area was stained reddish purple in older female dogs. Considering the report that says halo formation near the nuclei of the fibrocytes might be involved in the rupture of the anterior cruciate ligament, as well as epidemiological background of the ruptured anterior cruciate ligament, the granule, which was stained with Alcian blue-PAS double staining where the halo was observed, should be investigated [17].…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Study on Androgen Receptors in the Anterior Cruciate Ligament in Dogs

Ohno¹,

Goto²,

Owaki

et al. 2013

Okajimas Folia Anat. Jpn.

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Summary: Androgen is closely involved as the cause of rupture of anterior cruciate ligament (ACL) in human. In dogs, however, factors contributing to rupture of ACL remain unknown. In this study, expression of androgen receptor (AR) and histological distribution of blood vessels in ACL, and serum testosterone concentration were investigated in relation with age and sex to confirm whether canine ACL is an androgen-responsive tissue. Materials of ACL were obtained from 26 dogs: 12 young female Beagles, 2 old female mixed breeds, 9 young male Beagles, and 3 old male mixed breeds. In all canine ACL, positive AR expression was recognized in the nuclei of the fibrocytes, fibroblasts, synovial cells, and vascular endothelial cells of ACL. Expressions of AR were lesser in old males compared to the young males; however, females had no age difference in expression. Distributions of blood vessels in the synovial membrane of the ligament were fewer in old dogs both of males and females than youngs. Although distributions of vessels in the interstitium were apparently fewer in young females. Serum testosterone concentration was significantly higher in young males. Females had no age difference in the levels. From these results, it is suggested that canine ACL is an androgen-responsive tissue, and this consideration seems to closely relate to the epidemiological background that the incidence of rupture of ACL of dogs is higher in females than in males.

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Morphogenesis of Degenerative Changes Predisposing Dogs to Rupture of the Cranial Cruciate Ligament.

Cited by 41 publications

References 8 publications

Cellular and extracellular matrix changes in anterior cruciate ligaments during human knee aging and osteoarthritis

Cellular and extracellular matrix changes in anterior cruciate ligaments during human knee aging and osteoarthritis

Immunopathological mechanisms in dogs with rupture of the cranial cruciate ligament

Immunohistochemical Study on Androgen Receptors in the Anterior Cruciate Ligament in Dogs

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