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. 2014 Mar 17;15(3):4619-34.
doi: 10.3390/ijms15034619.

Testosterone reduces knee passive range of motion and expression of relaxin receptor isoforms via 5α-dihydrotestosterone and androgen receptor binding

Firouzeh Dehghan  1 , Sekaran Muniandy  2 , Ashril Yusof  3 , Naguib Salleh  4
Affiliations

Testosterone reduces knee passive range of motion and expression of relaxin receptor isoforms via 5α-dihydrotestosterone and androgen receptor binding

Firouzeh Dehghan et al. Int J Mol Sci. .

Abstract

Ovarian steroids such as estrogen and progesterone have been reported to influence knee laxity. The effect of testosterone, however, remains unknown. This study investigated the effect of testosterone on the knee range of motion (ROM) and the molecular mechanisms that might involve changes in the expression of relaxin receptor isoforms, Rxfp1 and Rxfp2 in the patella tendon and lateral collateral ligament of the female rat knee. Ovariectomized adult female Wistar rats received three days treatment with peanut oil (control), testosterone (125 and 250 μg/kg) and testosterone (125 and 250 μg/kg) plus flutamide, an androgen receptor blocker or finasteride, a 5α-reductase inhibitor. Duplicate groups received similar treatment however in the presence of relaxin (25 ng/kg). A day after the last drug injection, knee passive ROM was measured by using a digital miniature goniometer. Both tendon and ligament were harvested and then analysed for protein and mRNA expression for Rxfp1 and Rxfp2 respectively. Knee passive ROM, Rxfp1 and Rxfp2 expression were significantly reduced following treatment with testosterone. Flutamide or finasteride administration antagonized the testosterone effect. Concomitant administration of testosterone and relaxin did not result in a significant change in knee ROM as compared to testosterone only treatment; however this was significantly increased following flutamide or finasteride addition. Testosterone effect on knee passive ROM is likely mediated via dihydro-testosterone (DHT), and involves downregulation of Rxfp1 and Rxfp2 expression, which may provide the mechanism underlying testosterone-induced decrease in female knee laxity.

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Figures

Figure 1.
Figure 1.
Passive ROM of the rat knee following treatment with peanut oil (control), testosterone, testosterone plus FLU or FIN with and without relaxin. Our findings indicated that treatment with 125 and 250 μg/kg testosterone significantly reduced the knee ROM as compared to control. In the presence of relaxin, knee ROM in the control group was significantly higher than in the testosterone-treated group. Relaxin administration to the group treated with testosterone did not result in a significant increase in the passive knee ROM as compared to without relaxin. The presence of FLU and FIN significantly increase the knee ROM which was further increased following relaxin administration (p < 0.05). * p < 0.05 as compared to in the absence of relaxin; † p < 0.05 as compared to control; # p < 0.05 as compared to in the absence of FLU or FIN. C: control; R: relaxin; T125: 125 μg/kg/day testosterone; T250: 250 μg/kg/day testosterone; FLU: flutamide; FIN: finasteride.
Figure 2.
Figure 2.
Changes in Rxfp1 (A) and Rxfp2 (B) mRNA expression in the presence of FLU and FIN in the patellar tendon of steroid-replaced ovariectomised rats. Treatment with 125 and 250 μg/kg/day testosterone caused a significant decrease in Rxfp1 and Rxfp2 mRNA levels as compared to control. Administration of flutamide and finasteride significantly antagonized the inhibitory effect of testosterone on Rxfp1 and Rxfp2 expression with FLU effect relatively higher than FIN for Rxfp1, however no significant differences were noted for Rxfp2 mRNA. † p < 0.05 as compared to control; * p < 0.05 as compared to testosterone only treatment for the respective group. T125: 125 μg/kg/day testosterone; T250: 250 μg/kg/day testosterone; FLU: 10 mg/kg flutamide; FIN: 20 mg/kg finasteride.
Figure 3.
Figure 3.
The expression of Rxfp1 (A) and Rxfp2 (B) protein in the patellar tissue homogenate from ovariectomised rats treated with testosterone with and without FLU and FIN. A decrease in Rxfp1 protein expression was noted following testosterone treatment which was antagonized by FLU and FIN. The expression of Rxfp2 protein was reduced following testosterone treatment which was also antagonized by FLU and FIN. The antagonizing effect of FIN indicated that DHT and not testosterone mediates the inhibition of Rxfp1 and Rxfp2 protein expression (C) (Data were expressed as mean ± SEM, n = 6 per treatment group; T125: 125 μg testosterone; T250: 250 μg testosterone; FLU: 10 mg/kg flutamide; FIN: 20 mg/kg finasteride). † p < 0.05 as compared to control; * p < 0.05 as compared to testosterone only treatment for the respective group.
Figure 4.
Figure 4.
Changes in Rxfp1 (A) and Rxfp2 (B) mRNA expression in the lateral collateral ligament of steroid-replaced ovariectomised rats in the presence of FLU and FIN. Treatment with 125 and 250 μg/kg/day testosterone caused a decrease in Rxfp1 and Rxfp2 mRNA expression as compared to control (testosterone only treatment) (p < 0.05). Administration of flutamide and finasteride caused a significant increase in the expression of Rxfp1 and Rxfp2 with FLU inhibition was relatively greater than FIN for Rxfp1, however FIN inhibition was relatively higher than FLU for Rxfp2 mRNA expression. † p < 0.05 as compared to control; * p < 0.05 as compared to testosterone only treatment for the respective group.
Figure 5.
Figure 5.
The expression of Rxfp1 (A) and Rxfp2 (B) protein from the homogenate of lateral collateral ligaments of ovariectomised rats treated with 125 and 250 μg/kg testosterone with and without FLU and FIN administration. A dose-dependent decrease in Rxfp1 protein expression was noted following treatment with both doses of testosterone which was antagonized by FLU and FIN. Similarly, a decrease in Rxfp2 protein expression was observed following treatment with both doses of testosterone which was antagonized by FLU and FIN (C). Data were expressed as mean ± SEM, n = 6 per treatment group; T125: 125 μg testosterone; T250: 250 μg testosterone; FLU: 10 mg/Kg FLU; FIN: 20 mg/kg FIN. † p < 0.05 as compared to control; * p and * p < 0.05 as compared to testosterone only treatment for the respective group.
Figure 6.
Figure 6.
Measurement of rats’ knee ROM by a digital miniature goniometer (Patent IC/No: PI 2013701411) as shown above. The device consists of an arm that is attached to a sensor that detects changes in angle once the arm is rotated. The sensor is connected to the software that analyzes the angle using a Torque principle. Torque is defined as the tendency of a force to rotate an object around a fixed axis which is given by this formula: “τ = r Fsinθ” formula. r: rat leg length (r); F: force (A); θ: angle between the applied force and rat’s ROM (A and B distance).
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