Adipose tissue-derived mesenchymal stem cells (AT-MSCs) offer potential as a therapeutic option for chronic discogenic low back pain (LBP) because of their immunomodulatory functions and capacity for cartilage differentiation. The goal of this study was to assess the safety and tolerability of a single intradiscal implantation of combined AT-MSCs and hyaluronic acid (HA) derivative in patients with chronic discogenic LBP. We performed a single-arm phase I clinical trial with a 12-month follow-up and enrolled 10 eligible chronic LBP patients. Chronic LBP had lasted for more than 3 months with a minimum intensity of 4/10 on a visual analogue scale (VAS) and disability level ≥ 30% on the Oswestry Disability Index (ODI). The 10 patients underwent a single intradiscal injection of combined HA derivative and AT-MSCs at a dose of 2 × 107 cells/disc (n = 5) or 4 × 107 cells/disc (n = 5). Safety and treatment outcomes were evaluated by assessing VAS, ODI, Short Form-36 (SF-36), and imaging (lumbar spine X-ray imaging and MRI) at regular intervals over 1 year. No patients were lost at any point during the 1-year clinical study. We observed no procedure or stem cell-related adverse events or serious adverse events during the 1-year follow-up period. VAS, ODI, and SF-36 scores significantly improved in both groups receiving both low (cases 2, 4, and 5) and high (cases 7, 8, and 9) cell doses, and did not differ significantly between the two groups. Among six patients who achieved significant improvement in VAS, ODI, and SF-36, three patients (cases 4, 8, and 9) were determined to have increased water content based on an increased apparent diffusion coefficient on diffusion MRI. Combined implantation of AT-MSCs and HA derivative in chronic discogenic LBP is safe and tolerable. However, the efficacy of combined AT-MSCs and HA should be investigated in a randomized controlled trial in a larger population. ClinicalTrials.gov NCT02338271 . Registered 7 January 2015.

Tauroursodeoxycholic acid (TUDCA) is a US FDA-approved hydrophilic bile acid for the treatment of chronic cholestatic liver disease. In the present study, we investigate the effects of TUDCA on the proliferation and differentiation of osteoblasts and its therapeutic effect on a mice model of osteoporosis. Following treatment with different concentrations of TUDCA, cell viability, differentiation, and mineralization were measured. Three-month-old female C57BL/6 mice were randomly divided into three groups (n = 8 mice per group): (i) normal mice as the control group, (ii) ovariectomy (OVX) group (receiving phosphate-buffered saline (PBS) treatment every other day for 4 weeks), and (iii) OVX group with TUDCA (receiving TUDCA treatment every other day for 4 weeks starting 6 weeks after OVX). At 11 weeks post-surgery, serum levels of procollagen type I N-terminal propeptides (PINP) and type I collagen crosslinked C-telopeptides (CTX) were measured, and all mice were sacrificed to examine the distal femur by micro-computed tomography (CT) scans and histology. TUDCA (100 nM, 1 µM) significantly increased the proliferation and viability of osteoblasts and osteoblast differentiation and mineralization when used in vitro. Furthermore, TUDCA neutralized the detrimental effects of methylprednisolone (methylprednisolone-induced osteoblast apoptosis). In the TUDCA treatment group the PINP level was higher and the CTX level was lower, but these levels were not significantly different compared to the PBS treatment group. Micro-CT and histology showed that the TUDCA treatment group preserved more trabecular structures in the distal femur compared to the PBS treatment group. In addition, the TUDCA treatment group increased the percentage bone volume with respect to the total bone volume, bone mineral density, and mice distal femur trabeculae compared with the PBS treatment group. Taken together, our findings suggest that TUDCA may provide a favorable effect on bones and could be used for the prevention and treatment of osteoporosis.

Han SH, et al. J Korean Orthop Assoc. 2009 Apr;44(2):219-225. http://dx.doi.org/10.4055/jkoa.2009.44.2.219

Genetic factors have been shown to be a small but significant predictor for osteoporosis and osteoporotic fracture risk. We performed a case–control association study to determine the association between miR‐146a, miR‐149, miR‐196a2, and miR‐499 polymorphisms and osteoporotic vertebral compression fracture (OVCF) susceptibility. In total, 286 unrelated postmenopausal Korean women (57 with OVCFs, 55 with non‐OVCFs, and 174 healthy controls) were recruited. All subjects underwent dual energy X‐ray absorptiometry to determine BMD at the lumbar spine and femoral neck. We focused on four single nucleotide polymorphisms (SNPs) of pre‐miRNA sequences including miR‐146aC>G (rs2910164), miR‐149T>C (rs2292832), miR‐196a2T>C (rs11614913), and miR‐499A>G (rs3746444). Genotype frequencies of these four SNPs were determined using polymerase chain reaction‐restriction fragment length polymorphism analysis. The TT genotype of miR‐149aT>C was less frequent in subjects with OVCFs, suggesting a protective effect against OVCF risk (Odds ratio [OR], 0.435; 95% confidence interval [CI], 0.22–0.85, p = 0.014), whereas the miR‐146aCG/ miR‐196a2TC combined genotype was more frequent in OVCF patients (OR, 5.163; 95%CI, 1.057–25.21, p = 0.043), suggesting an increase in OVCF risk. Additionally, combinations of miR‐146a, ‐149, ‐196a2, and ‐449 showed a significant association with increased prevalence of OVCFs in postmenopausal women. In particular, the miR‐146aG/‐149T/‐196a2C/‐449G allele combination was significantly associated with an increased risk of OVCF (OR, 35.01; 95% CI, 1.919–638.6, p = 0.001). Our findings suggest that the TT genotype of miR‐149aT>C may contribute to decreased susceptibility to OVCF in Korean postmenopausal women. Conversely, the miR‐146aCG/ miR‐196a2TC combined genotype and the miR‐146aG/‐149T/‐196a2C/‐449G allele combination may contribute to increased susceptibility to OVCF. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:244–253, 2018.

It was reported that substance P had beneficial effects in the healing of acute tendon injury. However, the relationship between substance P and degenerative tendinopathy development remains unclear. The purpose of this study was to determine the role of substance P in the pathogenesis of tendinopathy. Healthy and tendinopathy tendon were harvested from human and tenocytes were cultured individually. The expression levels of genes associated with tendinopathy were compared. Next, substance P was exogenously administered to the healthy tenocyte and the effect was evaluated. The results showed that tendinopathy tenocytes had higher levels of COL3A1, MMP1, COX2, SCX, ACTA2, and substance P gene expression compared to healthy tenocytes. Next, substance P treatment on the healthy tenocyte displayed similar changes to that of the tendinopathy tenocytes. These differences between the two groups were also determined by Western blot. Additionally, cells with substance P had the tendinopathy change morphologically although cellular proliferation was significantly higher compared to that of the control group. In conclusion, substance P enhanced cellular proliferation, but concomitantly increased immature collagen (type 3 collagen). Substance P plays a crucial role in tendinopathy development and could be a future therapeutic target for treatment.

As life expectancy increases, the prevalence of osteoporosis is increasing. In addition to vitamin D which is well established to have an association with osteoporosis, B vitamins, such as thiamine, folate (vitamin B9), and cobalamin (vitamin B12), could affect bone metabolism, bone quality, and fracture risk in humans by influencing homocysteine/folate metabolism. Despite the crucial role of B vitamins in bone metabolism, there are few studies regarding associations between B vitamin-related genes and osteoporosis. In this study, we investigated the genetic association of four single nucleotide polymorphisms (SNPs) within the 3’-untranslated regions of vitamin B-related genes, including TCN2 (encodes transcobalamin II), CD320 (encodes transcobalamin II receptor), SLC19A1 (encodes reduced folate carrier protein 1), and SLC19A2 (encodes thiamine carrier 1), with osteoporosis and osteoporotic vertebral compression fracture (OVCF). We recruited 301 postmenopausal women and performed genotyping of CD320 rs9426 C>T, TCN2 rs10418 C>T, SLC19A1 rs1051296 G>T, and SLC19A2 rs16862199 C>T using a polymerization chain reaction-restriction fragment length polymorphism assay. There was a significantly higher incidence of both osteoporosis (AOR 5.019; 95% CI, 1.533–16.430, p < 0.05) and OVCF (AOR, 5.760; 95% CI, 1.480–22.417, p < 0.05) in individuals with genotype CD320 CT+TT and high homocysteine concentrations. Allele combination analysis revealed that two combinations, namely CD320 C-TCN2 T-SLC19A1 T-SLC19A2 C (OR, 3.244; 95% CI, 1.478–7.120, p < 0.05) and CD320 T-TCN2 C-SLC19A1 G-SLC19A2 C (OR, 2.287; 95% CI, 1.094–4.782, p < 0.05), were significantly more frequent among the osteoporosis group. Our findings suggest that SNPs within the CD320 gene in 3´-UTR may contribute to osteoporosis and OVCF occurrences in some individuals. Furthermore, specific allele combinations of CD320, TCN2, SLC19A1, and SLC19A2 may contribute to increased susceptibility to osteoporosis and OVCF.