Prospective study of histomorphometry,biochemical bone markers and bone densitometric response to pamidronate in β-thalassaemia presenting with osteopenia-osteoporosis syndrome

This study aimed to evaluate bone remodelling disorders in thalassaemia by using pamidronate (PD) infusion with or without hormone replacement therapy (HRT) as a diagnostic-therapeutic tool. In this prospective study, 24 adult thalassaemia major (TM) and 10 thalassaemia intermedia (TI) patients received either PD and HRT or HRT only (controls) for 3 years. Eugonadal patients with TI had PD only. Bone remodelling was assessed by dual energy X ray absorptiometry (DXA scan), type 1-collagen biochemical bone markers (BBM) and histomorphometry of iliac crest biopsy before and after PD. As a group, thalassaemics had a significant improvement in spinal and femoral bone mineral density Z scores following PD (P < 0·01) compared to the controls. Although BBM were comparable pre-therapy, they were significantly lower in the PD cohort (P < 0·001) compared to the control group. All patients had osteopenia, diminished osteoid formation and bone volume on histomorphometry pre-therapy with high turnover bone disease (HTO) in TM and low-turnover disease (LTO) in TI. In TM, bone volume improved significantly, whereas TI patients showed little or no response to PD. In conclusion, histomorphometry data suggest that TM patients have a distinct pathology of high turnover bone disease compared to TI patients, who have low-turnover disease.     

CHANGES IN LEVELS OF CARTILAGE OLIGOMERIC PROTEINASE AND URINARY C-TERMINAL TELOPEPTIDE OF TYPE II COLLAGEN IN SUBJECTS WITH KNEE OSTEOARTHRITIS AFTER DEXTROSE PROLOTHERAPY: A RANDOMIZED CONTROLLED TRIAL

ObjectiveTo assess the effects of dextrose prolotherapy in patients with knee osteoarthritis on the levels of serum cartilage oligomeric proteinase and urinary C-terminal telopeptide of type II collagen, and on the Western Ontario McMaster Universities Index and numerical rating scale score for pain.MethodsA randomized controlled trial, in which participants were randomly allocated into 2 groups, receiving injections of either hyaluronic acid or dextrose prolotherapy. The hyaluronic acid group received 5 injections, 1 each on weeks 1, 2, 3, 4 and 5, and the dextrose prolotherapy group received 3 injections, 1 each on weeks 1, 5 and 9. Serum cartilage oligomeric proteinase, urinary C-terminal telopeptide of type II collagen, Western Ontario McMaster Universities Index score, and numerical rating scale score for pain were measured at baseline and 3 weeks after the last injection. Comparative analysis was conducted using Wilcoxon test within groups and analysis of covariance (ANCOVA) test between groups.ResultsA total of 47 participants (21 allocated to hyaluronic acid, 26 allocated to dextrose prolotherapy) completed the protocol. Both interventions resulted in significant improvements in numerical rating scale scores for pain, total Western Ontario McMaster Universities Index scores, and its subscales score. However, the dextrose prolotherapy outperformed hyaluronic acid in numerical rating scale score for pain and level of urinary C-terminal telopeptide of type II collagen, with score changes differences of 0.93 (p = 0.042) and 0.34 (p = 0.048), respectively. No significant changes in level of serum cartilage oligomeric proteinase were found in either group.ConclusionDextrose prolotherapy is an alternative injection therapy for knee osteoarthritis, which was found to be associated with a significant reduction in urinary C-terminal telopeptide of type II collagen compared with hyaluronic acid injection. Neither injection method resulted in reduced serum cartilage oligomeric proteinase.LAY ABSTRACTKnee osteoarthritis is a common musculoskeletal disorder, which is one of the most frequent causes of disability in elderly people. To improve patients’ quality of life, prolotherapy has been developed as a non-operative treatment option for osteoarthritis. This study compared the effectiveness of dextrose prolotherapy with that of standard therapy using hyaluronic acid injections. Both interventions were effective in terms of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score improvement and numerical rating scale score changes. Cartilage repair was assessed by measuring levels of specific biomarkers of cartilage breakdown: urinary C-terminal telopeptide of type II collagen (uCTX-II) and serum cartilage oligomeric matrix protein (sCOMP). Dextrose prolotherapy was more effective than hyaluronic acid in reducing these biomarkers and decreasing patients’ pain. Dextrose prolotherapy is therefore recommended for use in patients with knee osteoarthritis, since it gives better results, is cost beneficial, and is suitable for use in low-resource settings. Dextrose prolotherapy may help to repair cartilage in knee OA, as it reduces the uCTX-II level.Key words: knee osteoarthritis, prolotherapy, hyaluronic acid, COMP, uCTX-II, functional outcome

Osteoarthritis (OA) is a highly prevalent musculoskeletal disorder, which is one of the most common causes of disability in elderly people (1–3). Several studies have demonstrated the effectiveness of hyaluronic acid (HA) injections, and recent guidelines have recommended their use in knee OA (4, 5). Xin has shown that intra-articular injection of HA (Adant®, Meiji Seika Pharma Co., Ltd., Tokyo, Japan. Manufactured by microbial fermentation and Artz®, Dispo: Seikagaku Corporation, Tokyo, Japan. Manufactured by the extraction of cockscomb), can significantly reduce both the visual analogue scale (VAS) score for pain and the Lequesne index (6). In contrast to these findings, however, a meta-analysis concluded that treatment of knee OA with HA injection did not result in a significantly different outcome from intra-articular placebo, despite the higher costs compared with other common non-operative intra-articular modalities (7).Regenerative therapy is an alternative approach that has been considered for OA, due to its potential to aid tissue regeneration, improve clinical manifestations, and repair damaged tissue structure, which is the underlying pathological condition in OA (8). An example of a currently developing regenerative approach is prolotherapy, an injection-based modality for treating chronic musculoskeletal pain through the use of substances such as dextrose, phenol-glycerine-glucose (P2G), or sodium morrhuate (9). Previous reports have demonstrated the effectivity of prolotherapy in significantly reducing the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score relative to saline injections and at-home exercise over 18 weeks after injection (10–12). In line with these findings, other reports have shown the promising effects of prolotherapy for tissue regeneration through radiological and arthroscopy-based assessments of cartilage repair (13).Cartilage oligomeric matrix protein (COMP) and urinary C-terminal telopeptide of type II collagen (uCTX-II) are specific biomarkers used to evaluate cartilage break-down in OA. Increased levels of these biomarkers can indicate the severity and prognosis of OA(14). Meanwhile, decrease in levels of both biomarkers has been assumed which indicates the improvement in cartilage (15). COMP and uCTX-II are recommended as promising specific bio-markers in OAcases based on Burden of disease, Investigative, prognostic, efficacy of intervention, and diagnostic (BIPED) criteria, as stated in a systematic review (16).Although previous reports have demonstrated promising potential of HA-based therapy and dextrose prolotherapy (DPT) in improving functional outcome in knee OA, none have compared the efficacy of those modalities in cartilage repair by assessing specific biomarkers, such as serum COMP (sCOMP) and uCTX-II. Hence, the aim of this study was to compare the effects of intra-articular HAand DPT on cartilage repair in knee OA, by measuring the changes in sCOMP and uCTX-II biomarkers.     

PELP1 signaling contributes to medulloblastoma progression by regulating the NF-κB pathway

Medulloblastoma (MB) is the most common and deadliest brain tumor in children. Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is a scaffolding protein and its oncogenic signaling is implicated in the progression of several cancers. However, the role of PELP1 in the progression of MB remains unknown. The objective of this study is to examine the role of PELP1 in the progression of MB. Immunohistochemical analysis of MB tissue microarrays revealed that PELP1 is overexpressed in the MB specimens compared to normal brain. Knockdown of PELP1 reduced cell proliferation, cell survival, and cell invasion of MB cell lines. The RNA-sequencing analysis revealed that PELP1 knockdown significantly downregulated the pathways related to inflammation and extracellular matrix. Gene set enrichment analysis confirmed that the PELP1-regulated genes were negatively correlated with nuclear factor-κB (NF-κB), extracellular matrix, and angiogenesis gene sets. Interestingly, PELP1 knockdown reduced the expression of NF-κB target genes, NF-κB reporter activity, and inhibited the nuclear translocation of p65. Importantly, the knockdown of PELP1 significantly reduced in vivo MB progression in orthotopic models and improved the overall mice survival. Collectively, these results suggest that PELP1 could be a novel target for therapeutic intervention in MB.