ABSTRACT
Spermidine has been known to inhibit the production of pro-inflammatory cytokines. However, there are no reports about anti-inflammatory effects of spermidine on osteoarthritis (OA). Herein, we examined whether OA progression could be delayed by intraperitoneal injection (i.p.) of spermidine in the anterior cruciate ligament transection (ACLT) and TNF-α induced arthritis (TIA) mouse models. During the process, human FLS cells (H-FLS) were used to investigate the potential ubiquitination mechanism of spermidine-mediated RIP1 in TNF-α-induced NF-κB/p65 signaling. We found that spermidine attenuated synovitis, cartilage degeneration and osteophyte formation, resulting in substantially lower OARSI scores and TNF-α scores in spermidine-treated ACLT and TIA mice. In terms of the mechanism, 9 µM spermidine did not affect the viability, proliferation, cell cycle and apoptosis of H-FLS, and exerted inhibitory effects by activating CYLD-mediated RIP1 deubiquitination on TNF-α-induced NF-κB/p65 signaling in H-FLS. From these data, we can conclude that spermidine attenuates OA progression by the inhibition of TNF-α-induced NF-κB pathway via the deubiquitination of RIP1 in FLS. Therefore, intake of spermidine could be a potential therapy for preventing OA.
Subject(s)
GTPase-Activating Proteins/metabolism , NF-kappa B/metabolism , Nuclear Pore Complex Proteins/metabolism , Osteoarthritis/metabolism , RNA-Binding Proteins/metabolism , Signal Transduction , Spermidine/pharmacology , Transcription Factor RelA/metabolism , Ubiquitination , Animals , Anterior Cruciate Ligament Injuries/pathology , Cartilage, Articular/drug effects , Cartilage, Articular/pathology , Cell Line , Deubiquitinating Enzyme CYLD/metabolism , Disease Models, Animal , Humans , Inflammation/pathology , Male , Mice, Inbred C57BL , Models, Biological , NF-kappa B/genetics , Osteoarthritis/pathology , Synovial Membrane/pathology , Tumor Necrosis Factor-alpha , Ubiquitination/drug effectsABSTRACT
OBJECTIVE: To investigate the influence of preoperative osteopenia/osteoporosis on periprosthetic bone loss after total hip arthroplasty (THA) and the efficiency of zoledronate (ZOL) treatment in periprosthetic bone preservation. METHODS: This multicenter, prospective cohort study was conducted in four centers between April 2015 and October 2017. Patients were assigned to Normal BMD, Osteopenia, and Osteoporosis+ZOL groups. Patients with osteopenia received daily oral calcium (600 mg/d) and vitamin D (0.5 µg/d), while patients in the Osteoporosis+ZOL group received additional ZOL annually (5 mg/year). Periprosthetic bone mineral density (BMD) in seven Gruen zones, radiographic parameters, Harris hip score, EuroQol 5-Dimensions (EQ-5D) score, and BMD in hip and spine were measured within 7 days, 3 months, 12 months postoperation and annually thereafter. RESULTS: A total of 266 patients were enrolled, while 81 patients that completed the first year follow-up were involved in the statistical analysis. The mean follow-up time was 1.3 years. There were significant decreases of mean BMD in total Gruen zones (-4.55%, P < 0.05) and Gruen zone 1 (-10.22%, P < 0.01) in patients with osteopenia during the first postoperative year. Patients in the Osteoporosis+ZOL group experienced a marked increase in BMD in Gruen zone 1 (+16%) at the first postoperative year, which had a significant difference when compared with the Normal BMD group (P < 0.05) and the Osteopenia Group (P < 0.001). Low preoperative BMD in hip and spine was predictive of bone loss in Gruen zone 1 at 12 months after THA in patients with normal BMD (R2 = 0.40, P < 0.05). CONCLUSIONS: Patients with osteopenia are prone to higher bone loss in the proximal femur after cementless total hip arthroplasty (THA). ZOL, not solely calcium and vitamin D, could prevent the accelerated periprosthetic bone loss after THA in patients with osteopenia and osteoporosis.
