The beneficial effect of intra-articular injection of losartan on the microfracture mediated cartilage repair is dose dependent

OBJECTIVES: 1. To determine the dosage and beneficial effects of intra-articular injection of losartan on microfracture-mediated cartilage repair and normal cartilage homeostasis. METHODS: Rabbits were divided into 5 groups (n=6):a microfracture group (MFX) and 4 different losartan treatment cohorts received varying dosages of IA losartan (0.1,1,10 and 100 mg/knee). An osteochondral defect (5mm) was created in the trochlear groove cartilage and 5 microfracture perforations were performed in the osteochondral defect. Both injured and contralateral knee joints were injected with losartan IA at days 0,14 and 28 after surgery. Rabbits were sacrificed at 6 weeks after surgery for analysis including gross observation, micro computed tomography, histology analysis and reverse transcription quantitative PCR. RESULTS: Micro computed tomography analysis and gross observation demonstrated comparable subchondral bone healing and hyaline-like appearing cartilage morphology in the 0.1, 1 and 10mg/knee losartan IA injection groups relative to the MFX group. Conversely, IA injection of losartan at 100mg/knee dosage showed neither bony defect healing nor cartilage repair. Histology revealed higher O’Driscoll scores and hyaline cartilage regeneration in the 1mg/knee cohort when compared to the MFX group. In contrast,100mg/knee losartan showed the lowest histology score and no cartilage repair. IA injection of losartan at the doses of 0.1,1 and 10mg/knee did not cause adverse effects on uninjured cartilage while 100mg/knee dose induced cartilage damage. Q-PCR results showed down-regulation of the TGFβ signaling pathway after losartan injection. CONCLUSIONS: Intra-articular injection of losartan at the dose 1mg/knee was most effective for enhancement of microfracture-mediated cartilage repair without adversely affecting uninjured cartilage. Conversely, high dose (100mg/knee) IA injection of losartan inhibited cartilage repair in osteochondral defect and was chondrotoxic to normal articular cartilage.