Jian Zhang

PURPOSE: To use meta-analysis techniques to evaluate the efficacy and safety of platelet-rich plasma (PRP) injections for the treatment knee of osteoarthritis (OA). METHODS: We performed a systematic literature search in PubMed, Embase, Scopus, and the Cochrane database through April 2016 to identify Level I randomized controlled trials that evaluated the clinical efficacy of PRP versus control treatments for knee OA. The primary outcomes were Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores. The primary outcomes were compared with their minimum clinically important differences (MCID)-defined as the smallest difference perceived as important by the average patient. RESULTS: We included 10 randomized controlled trials with a total of 1069 patients. Our analysis showed that at 6 months postinjection, PRP and hyaluronic acid (HA) had similar effects with respect to pain relief (WOMAC pain score) and functional improvement (WOMAC function score, WOMAC total score, International Knee Documentation Committee score, Lequesne score). At 12 months postinjection, however, PRP was associated with significantly better pain relief (WOMAC pain score, mean difference -2.83, 95% confidence interval [CI] -4.26 to -1.39, P = .0001) and functional improvement (WOMAC function score, mean difference -12.53, 95% CI -14.58 to -10.47, P < .00001; WOMAC total score, International Knee Documentation Committee score, Lequesne score, standardized mean difference 1.05, 95% CI 0.21-1.89, P = .01) than HA, and the effect sizes of WOMAC pain and function scores at 12 months exceeded the MCID (-0.79 for WOMAC pain and -2.85 for WOMAC function score). Compared with saline, PRP was more effective for pain relief (WOMAC pain score) and functional improvement (WOMAC function score) at 6 months and 12 months postinjection, and the effect sizes of WOMAC pain and function scores at 6 months and 12 months exceeded the MCID. We also found that PRP did not increase the risk of adverse events compared with HA and saline. CONCLUSIONS: Current evidence indicates that, compared with HA and saline, intra-articular PRP injection may have more benefit in pain relief and functional improvement in patients with symptomatic knee OA at 1 year postinjection. LEVEL OF EVIDENCE: Level I, meta-analysis of Level I studies.

Survival and stemness of bone marrow mesenchymal stem cells (BMSCs) in osteonecrotic areas are especially important in the treatment of early steroid-induced osteonecrosis of the femoral head (ONFH). We had previously used BMSCs to repair early steroid-induced ONFH, but the transplanted BMSCs underwent a great deal of stress-induced apoptosis and aging in the oxidative-stress (OS) microenvironment of the femoral-head necrotic area, which limited their efficacy. Our subsequent studies have shown that under OS, massive accumulation of damaged mitochondria in cells is an important factor leading to stress-induced apoptosis and senescence of BMSCs. The main reason for this accumulation is that OS leads to upregulation of protein 53 (P53), which inhibits mitochondrial translocation of Parkin and activation of Parkin's E3 ubiquitin ligase, which decreases the level of mitophagy and leads to failure of cells to effectively remove damaged mitochondria. However, P53 downregulation can effectively reverse this process. Therefore, we upregulated Parkin and downregulated P53 in BMSCs. We found that this significantly enhanced mitophagy in BMSCs, decreased the accumulation of damaged mitochondria in cells, effectively resisted stress-induced BMSCs apoptosis and senescence, and improved the effect of BMSCs transplantation on early steroid-induced ONFH.

Novel therapies for the treatment of early steroid-induced osteonecrosis of the femoral head (SONFH) are urgently needed in orthopedics. Transplantation of bone marrow mesenchymal stem cells (BMSCs) provides new strategies for treating this condition at the early stage. However, stress-induced apoptosis of BMSCs transplanted into the femoral head necrotic area limits the efficacy of BMSC transplantation. Inhibiting BMSC apoptosis is key to improving the efficacy of this procedure. In our previous studies, we confirmed that Parkinson disease protein 7 (PARK7) is active in antioxidant defense and can clear reactive oxygen species (ROS), protect the mitochondria, and impart resistance to stress-induced apoptosis in BMSCs. In this study, we investigated the mechanism driving this PARK7-mediated resistance to apoptosis in BMSCs. Our results indicate that PARK7 promoted the disintegration of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like echinacoside-associated protein 1 (Keap1) complex. The free Nrf2 then entered the nucleus and activated the genetic expression of manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GPx), and other antioxidant enzymes that clear excessive ROS, thereby protecting BMSCs from stress-induced apoptosis. To further explore whether PARK7-mediated resistance to stress-induced apoptosis could improve the efficacy of BMSC transplantation in early-stage SONFH, we transplanted BMSCs-overexpressing PARK7 into rats with early-stage SONFH. We then evaluated the survival of transplanted BMSCs and bone regeneration in the femoral head necrotic area of these rats. The results indicated that PARK7 promoted the survival of BMSCs in the osteonecrotic area and improved the transplantation efficacy of BMSCs on early-stage SONFH. This study provides new ideas and methods for resisting the stress-induced apoptosis of BMSCs and improving the transplantation effect of BMSCs on early-stage SONFH.

BACKGROUND: Nontraumatic osteonecrosis of the femoral head (NONFH) is a common, progressive, and refractory orthopaedic disease. Decreased osteogenesis and angiogenesis are considered the main factors in the pathogenesis of NONFH. We aimed to figure out whether exosomes and exosomal miRNA from necrotic bone tissues of patients with NONFH are involved in the pathogenesis of NONFH and reveal the underlying mechanisms. METHODS: RT-PCR and western blotting (WB) were used to detect the expression of osteogenic, adipogenic, and angiogenic markers. ALP staining and Alizarin Red S (ARS) staining were used to evaluate osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). Oil Red O staining was performed to assess the adipocyte deposition. A tube formation assay was used to study angiogenesis of human umbilical vascular endothelial cells (HUVECs). H&E staining and immunohistochemistry (IHC) staining were used to detect the effect of the NONFH exosomes in vivo. MicroRNA sequencing was conducted to identify potential regulators in the NONFH exosomes. The target relationship between miR-100-5p and BMPR2 was predicted and confirmed by a dual luciferase reporter assay and WB. RESULTS: The NONFH exosomes reduced the osteogenic differentiation of hBMSCs and angiogenesis of HUVECs. In addition, the injection of the NONFH exosomes caused thinning and disruption of bone trabeculae in the femoral heads of rats. MiR-100-5p expression was upregulated in the NONFH exosomes and inhibited the osteogenesis of hBMSCs and angiogenesis of HUVECs by targeting BMPR2 and suppressing the BMPR2/SMAD1/5/9 signalling pathway. Silencing miR-100-5p expression rescued the reduction in osteogenesis and angiogenesis caused by the NONFH exosomes by activating the BMPR2/SMAD1/5/9 signalling pathway. CONCLUSION: The NONFH exosomal miR-100-5p can lead to NONFH-like damage by targeting BMPR2 and suppressing the BMPR2/SMAD1/5/9 signalling pathway, which may be involved in the pathophysiological mechanisms of nontraumatic osteonecrosis of the femoral head (NONFH).