CD206+ M2-like macrophages protect against intervertebral disc degeneration partially by targeting R-spondin-2.

OBJECTIVE: This study aimed to explore the specific function of M2 macrophages in intervertebral disc degeneration (IDD). METHODS: Intervertebral disc (IVD) samples from normal (n = 4) and IDD (n = 6) patients were collected, and the expression of M2-polarized macrophage marker, CD206, was investigated using immunohistochemical staining. Nucleus pulposus cells (NPCs) in a TNF-α environment were obtained, and a mouse caudal IVD puncture model was established. Mice with Rheb deletions, specifically in the myeloid lineage, were generated and subjected to surgery-induced IDD. IDD-induced damage and cell apoptosis were measured using histological scoring, X-ray imaging, immunohistochemical staining, and TdT-mediated dUTP nick end labeling (TUNEL) assay. Finally, mice and NPCs were treated with R-spondin-2 (Rspo2) or anti-Rspo2 to investigate the role of Rspo2 in IDD. RESULTS: Accumulation of CD206 in human and mouse IDD tissues was detected. Rheb deletion in the myeloid lineage (RheBcKO) increased the number of CD206+ M2-like macrophages (mean difference 18.6% [15.7-21.6%], P < 0.001), decreased cell apoptosis (mean difference -15.6% [-8.9 to 22.2%], P = 0.001) and attenuated the IDD process in the mouse IDD model. NPCs treated with Rspo2 displayed increased extracellular matrix catabolism and apoptosis; co-culture with a conditioned medium derived from RheBcKO mice inhibited these changes. Anti-Rspo2 treatment in the mouse caudal IVD puncture model exerted protective effects against IDD. CONCLUSIONS: Promoting CD206+ M2-like macrophages could reduce Rspo2 secretion, thereby alleviating experimental IDD. Rheb deletion may help M2-polarized macrophages accumulate and attenuate experimental IDD partially by inhibiting Rspo2 production. Hence, M2-polarized macrophages and Rspo2 may serve as therapeutic targets for IDD.

Influence of macrophage polarization in herniated nucleus pulposus tissue on clinical efficacy after lumbar discectomy.

Background: Low back pain or sciatic pain because of lumbar intervertebral disc herniation (LDH) is caused by mechanical compression and/or an inflammatory component on the nerve root. However, it is difficult to define to what extent each component contributes to the pain. This study attempted to explore the effects of macrophage polarization on clinical symptoms in patients experiencing LDH after surgery, and investigated the association between macrophage cell percentages and clinical efficacy. Methods: This study retrospectively harvested nucleus pulposus (NP) tissue samples from 117 patients. Clinical symptoms and efficacy using the visual analog scale (VAS) and Oswestry Disability Index (ODI) were evaluated at different time points preoperatively and postoperatively. CD68, CCR7, CD163, and CD206 were selected as macrophage phenotypic markers. Results: Seventy-six samples showed positive expression of macrophage markers in NP samples of patients with LDH, whereas 41 patients displayed negative results. No significant differences were detected between the two groups, involvement of several demographic data, and preoperative clinical findings. With respect to the macrophage-positive group, no significant correlation was detected between the positive rate of the four markers and the VAS score or ODI after surgery. However, patients with NP samples positive for CD68 and CCR7 expression showed significantly lower VAS scores 1 week after surgery compared with those in the negative group. Moreover, the improvement in VAS score showed a strong positive correlation with CD68- and CCR7-positive cell percentages. Conclusions: Our results indicated that pro-inflammatory M1 macrophages may be associated with the reduction of chronic pain after surgery. Therefore, these findings contribute to better personalized pharmacological interventions for patients with LDH, considering the heterogeneity of pain.

[Therapeutic effect and mechanism of silver needle heat conduction therapy combined with loxoprofen sodium patch in patients with knee osteoarthritis].

OBJECTIVE: To observe the clinical efficacy of silver needle heat conduction therapy combined with loxoprofen sodium patch in the treatment of knee osteoarthritis (KOA). METHODS: A total of ninety-two patients with KOA were randomly and equally divided into loxoprofen sodium group and silver needle heat conduction therapy + loxoprofen sodium (combination) group, with 46 cases in each group. Patients of the combination group were treated with silver needle heat conduction therapy combined with loxoprofen sodium patch, while those of the loxoprofen sodium group were treated with loxoprofen sodium patch. The treatment was conducted for 4 weeks. The Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), bone metabolism index ï¼»including bone gla protein (BGP), bone-specific alkaline phosphatase (BALP), tartrate resistant acid phosphatase isomer (TRACP)-5bï¼½, and inflammation factors ï¼»including the tumor necrosis factor-α (TNF-α), transforming growth factor-ß (TGF-ß), interleukin-1ß (IL-1ß)ï¼½ were observed before and after treatment. The therapeutic effect was assessed after the treatment. RESULTS: After the treatment, the total scores of WOMAC, the levels of serum TRACP-5b, TNF-α and IL-1ß were significantly decreased (P<0.01), while the levels of serum BGP, BALP, and TGF-ß were significantly increased (P<0.01) in the two groups compared with their own pre-treatment. Silver needle plus loxoprofen sodium was more effective in reducing WOMAC score, TRACP-5b, TNF-α, IL-1ß level (P<0.01), and up-regulating BGP, BALP, and TGF-ß level (P<0.01) than loxoprofen. Of the 46 cases in the loxoprofen sodium and combination groups, 33 and 41 were effective, with the effective rate being 71.7% and 89.1%, respectively. The comprehensive therapeutic effect of the combination group was significantly superior to that of the loxoprofen group (P<0.05). CONCLUSION: Silver needle heat conduction therapy combined with loxoprofen sodium can effectively treat KOA, its mechanism may be related to alleviating inflammation and improving bone metabolism.

MicroRNA-19b downregulates insulin 1 through targeting transcription factor NeuroD1.

MiR-17-92 cluster miRNAs are disclosed to contribute to the development of multiple organs and tumorigenesis, but their roles in pancreas development remains unclear. In this study, we found that miR-19b, a member of miR-17-92, was highly expressed in the pancreatic progenitor cells, and miR-19b could target the 3' UTR of NeuroD1 mRNA to decrease its protein and mRNA levels. Functional analysis showed that miR-19b exerted little effect on the proliferation of pancreatic progenitors, whereas it inhibited the expression of insulin 1, but not insulin 2 in MIN6 cells. These results suggest that miR-19b can downregulate insulin 1 expression through targeting transcription factor NeuroD1, and thus regulate the differentiation and function of ß-cells.

[The roles of miR-17-92 cluster in mammal development and tumorigenesis].

MicroRNAs (miRNAs) are a new class of small, non-coding RNAs that regulate gene expression. The base pairing interactions between miRNAs and their target mRNAs, often within the 3'-untranslated region (UTR) of target genes, result in the degradation of target mRNAs or repression of their translation. MiRNAs regulate a diverse range of physiological processes, including cell differentiation and proliferation, mammalian development and human disease. Many studies have shown that miR-17-92 cluster, which encodes miR-17-5p, miR-17-3p, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92-1, is expressed in many mammalian tissues. This cluster contributes to the development of heart, lung, blood vessel, and immune system. In addition, it can induce tumorigenesis, such as lymphoma and vascularized tumor as an oncogene. However, miR-17-92 cluster proved to suppress breast cancer cell proliferation and tumor colony formation as a tumor suppressor. This paper reviews the roles of miR-17-92 cluster in mammal development and the relationship between miR-17-92 cluster and tumorigenesis.