Development of Osteoarthritis in the Knee Joints of Wistar Rats After Strenuous Running Exercise in a Running Wheel by Intracranial Self-Stimulation

Pap, G.; Eberhardt, René; Stürmer, Immo; Machner, A.; Schwarzberg, H; Roessner, Albert; Neumann, Wolfram

doi:10.1016/s0344-0338(98)80010-1

Cited by 91 publications

(92 citation statements)

References 22 publications

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“…Earlier studies in mice, rats and dogs have found that, in contrast to mild exercise, moderate or strenuous exercise produced degenerative cartilage changes of the knee [1, 16,28]. Our findings are comparable to those of Machner et al who used a similar study design in rats with partial knee joint denervation with capsaicin and strenuous treadmill running ( 1 h/day, 5 daydweek).…”

Section: Effects Of Exercise On Joint Degenerutionsupporting

confidence: 87%

Selective joint denervation promotes knee osteoarthritis in the aging rat

Salo

Hogervorst

Seerattan

et al. 2002

Journal Orthopaedic Research

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Osteoarthritis is the most common joint disorder with aging, but its cause is unknown. Mice lose joint afferents with aging, and this loss precedes development of osteoarthritis. We hypothesized a loss of joint afferents is involved in the pathogenesis of osteoarthritis.To test this hypothesis, we denervated knee joints of 16 rats at age 2 months, by intra-articular injection o f an immunotoxin. The imrnunotoxin killed neurons after retrograde axonal transport to the cell body. At 16 or 24 months follow-up, each joint was histologically assessed and assigned an osteoarthritis score.At follow-up, the number of joint afferents had spontaneously decreased by 42% in control knees and 69%~ in denervated knees. We found that control knees developed osteoarthritic changes with aging. However, denervated knees had far more severe changes, as evidenced by a 54% higher average osteoarthritis score than control knees ( P = 0.0016, both groups 16 knees).These results suggest a loss of afferents predisposes a joint to osteoarthritis. We propose the spontaneous loss o f neurons with aging may be a normal developmental process. To explain the mechanism causing osteoarthritis, we suggest denervation permits aberrant joint loading, either by disturbing neuromuscular joint control, or by inducing joint laxity after neurogenic loss of tissue homeostasis.

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Section: Effects Of Exercise On Joint Degenerutionsupporting

confidence: 87%

Selective joint denervation promotes knee osteoarthritis in the aging rat

Salo

Hogervorst

Seerattan

et al. 2002

Journal Orthopaedic Research

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Section: Strenuous Running Of Ratsmentioning

confidence: 99%

“…Strenuous running of rats enhances mechanical stress on weight bearing joints, inducing OA of the knees. 2,3 This model requires no surgery or drugs, making it possible to detect subtle changes accompanying OA.Bone morphogenetic proteins (BMPs) have a variety of biological effects including enhancement of cartilage repair. 4 Among BMPs, BMP-7 is especially attractive, because it is one of two BMPs already approved for clinical use in various applications by the FDA.…”

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confidence: 99%

“…Rats were forced to run 15 km in 3 weeks or 30 km in 6 weeks. 2,3 All experiments were conducted in accordance with our institutional guidelines for the care and use of experimental animals.Intra-Articular Injection of BMP-7 rhBMP-7 lyophilized in 5% lactose buffer (Stryker Biotech, Hopkinton, MA) was dissolved in phosphate-buffered saline (PBS). BMP-7 (250 ng) in 100 mL PBS was injected into the right knee with a 27-gauge needle on a 1.0 mL syringe through the lateral infrapatellar area toward the intercondylar space of the femur in a deep knee flexed position.…”

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confidence: 99%

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confidence: 99%

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Periodic knee injections of BMP‐7 delay cartilage degeneration induced by excessive running in rats

Sekiya

Tang

Hayashi

et al. 2009

Journal Orthopaedic Research

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Strenuous running of rats enhances mechanical stress on the knee, thereby inducing degeneration of articular cartilage. Bone morphogenetic protein-7 (BMP-7) has an inhibitory effect on cartilage degeneration, suggesting its usefulness for human osteoarthritis patients. However, its mode of administration should be investigated. We examined whether weekly knee injections of BMP-7 delayed the progression of cartilage degeneration. Wistar rats were forced to run 30 km in 6 weeks on a rodent treadmill, and BMP-7 was injected weekly into the knee. Macroscopically and histologically, this strenuous running regimen induced cartilage degeneration. Weekly injections of 250 ng BMP-7 delayed the progression of cartilage degeneration. Immunohistochemically, in the control knee, type II collagen expression decreased, while BMP-7 expression in chondrocytes slightly increased. Interestingly, weekly injection of BMP-7 increased BMP-7 expression even 9 days after the final injection. Disulfate disaccharide keratan sulfate in serum transiently increased in the control group, while it remained at a low level in the BMP-7 group. Weekly BMP-7 injection increased BMP-7 expression in chondrocytes and its effect seemed to last more than 7 days. The effect of BMP-7 could be monitored by serum keratan sulfate concentration. Periodical injections of BMP-7 delayed progression of cartilage degeneration induced by excessive running in rats. Keywords: BMP-7; articular cartilage; strenuous running; keratan sulfate; weekly injection Osteoarthritis (OA) in the knees constitutes an increasingly common medical problem for aging people. 1 Mechanical stress is one of the factors contributing to the progression of OA. Strenuous running of rats enhances mechanical stress on weight bearing joints, inducing OA of the knees. 2,3 This model requires no surgery or drugs, making it possible to detect subtle changes accompanying OA.Bone morphogenetic proteins (BMPs) have a variety of biological effects including enhancement of cartilage repair. 4 Among BMPs, BMP-7 is especially attractive, because it is one of two BMPs already approved for clinical use in various applications by the FDA. Recent data from an anterior cruciate ligament transection model in rabbits demonstrated that continuous intraarticular infusion of BMP-7 had a protective effect on cartilage degeneration, 5 suggesting the possible utility of BMP-7 as a treatment for human OA patients. However, given the challenges associated with clinical delivery by continuous infusion, further consideration should be given to the mode of administration.We speculated that periodic injections of BMP-7 into the knee joint might suppress the loss of cartilage matrix and consequently prevent OA progression. The purpose of this study was to examine whether weekly knee injections of BMP-7 delay development of OA and to investigate the possible mechanisms for this action in a strenuous running model of OA in rats. MATERIALS AND METHODS Strenuous Running of RatsWistar rats at 15-16 weeks of age (Sankyo L...

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Development and characteristics of a synovial-like interface membrane around cemented tibial hemiarthroplasties in a novel rat model of aseptic prosthesis loosening

Pap

Machner

Rinnert

et al. 2001

Arthritis & Rheumatism

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Objective Aseptic prosthesis loosening (APL) is related to the formation and aggressive growth of a synovial‐like interface membrane (SLIM) between prosthesis and bone. However, investigation of the early phases of SLIM development in humans presents major difficulties. This study was undertaken to develop and characterize the usefulness of a novel animal model of APL that is based on an established model of defined exercise in a running wheel by Wistar rats that have been subjected to intracranial self‐stimulation (ICSS). Methods Cemented tibial hemiarthroplasties were implanted into the left knees of 7 male Wistar rats. After 2 weeks, exercise in a running wheel was started in all rats, with a running‐load of 2 hours/day for 5 days/week. Six months postoperatively, the knee joints were removed, decalcified, and embedded in paraffin. Histologic evaluation on hematoxylin and eosin–stained sections was performed to investigate the development of a SLIM and the presence of cement debris particles. To characterize the SLIM on a molecular level and investigate growth‐regulating factors, the expression of transforming growth factor β (TGFβ) and the antiapoptotic molecule Bcl‐2 was analyzed by immunohistochemistry. Results Although the prostheses appeared mechanically stable after 6 months, the development of SLIM with areas of bone resorption was seen in all samples. Resembling human SLIM, these membranes consisted of loose fibrous tissue, with cement debris particles located particularly at sites originally attached to the prostheses. Immunohistochemistry studies revealed the expression of TGFβ and Bcl‐2 in all specimens. Interestingly, staining for TGFβ and Bcl‐2 was restricted to areas where the SLIM were attached to bone. In contrast, there was only negligible expression of both proteins at sites adjacent to the prostheses. Conclusion Our findings demonstrate that the ICSS Wistar rat model constitutes a feasible tool for studying early stages of APL, and specifically the effect of defined running exercise on SLIM formation. The results further suggest that both cellular proliferation, as stimulated by TGFβ, and altered apoptosis contribute to early stages of SLIM formation. The expression patterns of TGFβ and Bcl‐2 indicate that the growth of the SLIM is initiated and promoted from the bone rather than from the prosthesis.

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Development of Osteoarthritis in the Knee Joints of Wistar Rats After Strenuous Running Exercise in a Running Wheel by Intracranial Self-Stimulation

Cited by 91 publications

References 22 publications

Selective joint denervation promotes knee osteoarthritis in the aging rat

Selective joint denervation promotes knee osteoarthritis in the aging rat

Periodic knee injections of BMP‐7 delay cartilage degeneration induced by excessive running in rats

Development and characteristics of a synovial-like interface membrane around cemented tibial hemiarthroplasties in a novel rat model of aseptic prosthesis loosening

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