Does anxiety influence outcome measurements in ankle replacement patients?

BACKGROUND: Total ankle arthroplasty (TAA) is increasingly used to treat end-stage ankle arthritis to restore ankle functional outcomes and alleviate pain. This treatment outcome may be influenced by pre-morbid patient anxiety. METHODS: Twenty-five Infinity TAA implants were prospectively followed post-operatively with a mean follow-up time of 34.18 months. Demographic, clinical, and functional outcomes were assessed. Analysis was performed on the effect of anxiety, reported by the HADS, on patient-perceived postoperative pain, functioning, and quality of life. RESULTS: Postoperative the PROMs and Range of Motion (ROM) improved significantly. Linear regression analysis and Pearson correlation showed a significant negative effect of anxiety on the postoperative patient-reported outcome measurements (EQ-5D-5L, VAS, and MOxFQ) at the end of follow-up. CONCLUSION: Good functional, clinical, and radiographic results were observed in this prospective cohort study. Anxiety had a negative influence on the outcome of the patient-reported outcome measurements (EQ-5D-5L and MOxFQ) postoperatively. LEVEL OF EVIDENCE: Level III, prospective cohort study.

Development of a cyclic-inverso AHSG/Fetuin A-based peptide for inhibition of calcification in osteoarthritis.

OBJECTIVE: Ectopic calcification is an important contributor to chronic diseases, such as osteoarthritis. Currently, no effective therapies exist to counteract calcification. We developed peptides derived from the calcium binding domain of human Alpha-2-HS-Glycoprotein (AHSG/Fetuin A) to counteract calcification. METHODS: A library of seven 30 amino acid (AA) long peptides, spanning the 118 AA Cystatin 1 domain of AHSG, were synthesized and evaluated in an in vitro calcium phosphate precipitation assay. The best performing peptide was modified (cyclic, retro-inverso and combinations thereof) and evaluated in cellular calcification models and the rat Medial Collateral Ligament Transection + Medial Meniscal Tear (MCLT + MMT) osteoarthritis model. RESULTS: A cyclic peptide spanning AA 1-30 of mature AHSG showed clear inhibition of calcium phosphate precipitation in the nM-pM range that far exceeded the biological activity of the linear peptide variant or bovine Fetuin. Biochemical and electron microscopy analyses of calcium phosphate particles revealed a similar, but distinct, mode of action in comparison with bFetuin. A cyclic-inverso variant of the AHSG 1-30 peptide inhibited calcification of human articular chondrocytes, vascular smooth muscle cells and during osteogenic differentiation of bone marrow derived stromal cells. Lastly, we evaluated the effect of intra-articular injection of the cyclic-inverso AHSG 1-30 peptide in a rat osteoarthritis model. A significant improvement was found in histopathological osteoarthritis score and animal mobility. Serum levels of IFNγ were found to be lower in AHSG 1-30 peptide treated animals. CONCLUSIONS: The cyclic-inverso AHSG 1-30 peptide directly inhibits the calcification process and holds the potential for future application in osteoarthritis.

Direct comparison of non-osteoarthritic and osteoarthritic synovial fluid-induced intracellular chondrocyte signaling and phenotype changes.

OBJECTIVE: Since the joint microenvironment and tissue homeostasis are highly dependent on synovial fluid, we aimed to compare the essential chondrocyte signaling signatures of non-osteoarthritic vs end-stage osteoarthritic knee synovial fluid. Moreover, we determined the phenotypic consequence of the distinct signaling patterns on articular chondrocytes. METHODS: Protein profiling of synovial fluid was performed using antibody arrays. Chondrocyte signaling and phenotypic changes induced by non-osteoarthritic and osteoarthritic synovial fluid were analyzed using a phospho-kinase array, luciferase-based transcription factor activity assays, and RT-qPCR. The origin of osteoarthritic synovial fluid signaling was evaluated by comparing the signaling responses of conditioned media from cartilage, synovium, infrapatellar fat pad and meniscus. Osteoarthritic synovial fluid induced pathway-phenotype relationships were evaluated using pharmacological inhibitors. RESULTS: Compared to non-osteoarthritic synovial fluid, osteoarthritic synovial fluid was enriched in cytokines, chemokines and growth factors that provoked differential MAPK, AKT, NFκB and cell cycle signaling in chondrocytes. Functional pathway analysis confirmed increased activity of these signaling events upon osteoarthritic synovial fluid stimulation. Tissue secretomes of osteoarthritic cartilage, synovium, infrapatellar fat pad and meniscus activated several inflammatory signaling routes. Furthermore, the distinct pathway signatures of osteoarthritic synovial fluid led to accelerated chondrocyte dedifferentiation via MAPK/ERK signaling, increased chondrocyte fibrosis through MAPK/JNK and PI3K/AKT activation, an elevated inflammatory response mediated by cPKC/NFκB, production of extracellular matrix-degrading enzymes by MAPK/p38 and PI3K/AKT routes, and enabling of chondrocyte proliferation. CONCLUSION: This study provides the first mechanistic comparison between non-osteoarthritic and osteoarthritic synovial fluid, highlighting MAPKs, cPKC/NFκB and PI3K/AKT as crucial OA-associated intracellular signaling routes.

Ribosomal RNA-based epitranscriptomic regulation of chondrocyte translation and proteome in osteoarthritis.

OBJECTIVE: Osteoarthritis-related cartilage extracellular matrix remodeling is dependent on changes in chondrocyte protein expression. Yet, the role of ribosomes in chondrocyte translation regulation is unknown. In this exploratory study, we investigated ribosomal RNA (rRNA) epitranscriptomic-based ribosome heterogeneity in human articular chondrocytes and its relevance for osteoarthritis. METHODS: Sequencing-based rRNA 2'-O-methylation profiling analysis (RiboMethSeq) was performed on non-OA primary human articular chondrocytes (n = 5) exposed for 14 days to osteoarthritic synovial fluid (14 donors, pooled, 20% v/v). The SW1353 SNORD71 KO cell pool was generated using LentiCRISPRv2/Cas9. The mode of translation initiation and fidelity were determined by dual-luciferase reporters. The cellular proteome was analyzed by LC-MS/MS and collagen type I protein expression was evaluated by immunoblotting. Loading of COL1A1 mRNA into polysomes was determined by sucrose gradient ultracentrifugation and fractionation. RESULTS: We discovered that osteoarthritic synovial fluid instigates site-specific changes in the rRNA 2'-O-me profile of primary human articular chondrocytes. We identified five sites with differential 2'-O-me levels. The 2'-O-me status of 5.8S-U14 (one of identified differential 2'-O-me sites; decreased by 7.7%, 95% CI [0.9-14.5%]) was targeted by depleting the level of its guide snoRNA SNORD71 (50% decrease, 95% CI [33-64%]). This resulted in an altered ribosome translation modus (e.g., CrPV IRES, FC 3, 95% CI [2.2-4.1]) and promoted translation of COL1A1 mRNA which led to increased levels of COL1A1 protein (FC 1.7, 95% CI [1.3-2.0]). CONCLUSIONS: Our data identify a novel concept suggesting that articular chondrocytes employ rRNA epitranscriptomic mechanisms in osteoarthritis development.

Unravelling the Basic Calcium Phosphate crystal-dependent chondrocyte protein secretome; a role for TGF-ß signaling.

OBJECTIVE: Basic Calcium Phosphate (BCP) crystals play an active role in the progression of osteoarthritis (OA). However, the cellular consequences remain largely unknown. Therefore, we characterized for the first time the changes in the protein secretome of human OA articular chondrocytes as a result of BCP stimulation using two unbiased proteomic analysis methods. METHOD: Isolated human OA articular chondrocytes were stimulated with BCP crystals and examined by Quantitative Reverse Transcription PCR (RT-qPCR) and enzyme-linked immune sorbent assay (ELISA) after twenty-four and forty-eight hours. Forty-eight hours conditioned media were analyzed by label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) and an antibody array. The activity of BCP dependent Transforming Growth Factor Beta (TGF-ß) signaling was analyzed by RT-qPCR and luciferase reporter assays. The molecular consequences regarding BCP-dependent TGF-ß signaling on BCP-dependent Interleukin 6 (IL-6) were investigated using specific pathway inhibitors. RESULTS: Synthesized BCP crystals induced IL-6 expression and secretion upon stimulation of human articular chondrocytes. Concomitant induction of catabolic gene expression was observed. Analysis of conditioned media revealed a complex and diverse response with a large number of proteins involved in TGF-ß signaling, both in activation of latent TGF-ß and TGF-ß superfamily members, which were increased compared to non-stimulated OA chondrocytes. Activity of this BCP driven TGF-ß signaling was confirmed by increased activity of expression of TGF-ß target genes and luciferase reporters. Inhibition of BCP driven TGF-ß signaling resulted in decreased IL-6 expression and secretion with a moderate effect on catabolic gene expression. CONCLUSION: BCP crystal stimulation resulted in a complex and diverse chondrocyte protein secretome response. An important role for BCP-dependent TGF-ß signaling was identified in development of a pro-inflammatory environment.

Synovial fluid from end-stage osteoarthritis induces proliferation and fibrosis of articular chondrocytes via MAPK and RhoGTPase signaling.

OBJECTIVES: Alterations in the composition of synovial fluid have been associated with adverse effects on cartilage integrity and function. Here, we examined the phenotypic and proliferative behavior of human articular chondrocytes when cultured in vitro for 13 days with synovial fluid derived from end-stage osteoarthritis patients. MATERIALS AND METHODS: Chondrocyte proliferation and phenotypical changes induced by osteoarthritic synovial fluid were analyzed using DNA staining, RT-qPCR, immunostainings, and immunoblotting. The molecular mechanisms by which osteoarthritic synovial fluid induced fibrosis and proliferation were studied using a phospho-protein antibody array and luciferase-based transcription factor activity assays. Specific pathway inhibitors were used to probe the involvement of pathways in fibrosis and proliferation. RESULTS: Prolonged stimulation with osteoarthritic synovial fluid sustained chondrocyte proliferation and induced profound phenotypic changes, favoring a fibrotic over a chondrogenic or hypertrophic phenotype. A clear loss of chondrogenic markers at both the transcriptional and protein level was observed, while expression of several fibrosis-associated markers were upregulated over time. Phospho-kinase analysis revealed activation of MAPK and RhoGTPase signaling pathways by osteoarthritic synovial fluid, which was confirmed by elevated transcriptional activity of Elk-1 and SRF. Inhibitor studies revealed that ERK played a central role in the loss of chondrocyte phenotype, while EGFR and downstream mediators p38, JNK and Rac/Cdc42 were essential for fibrosis-associated collagen expression. Finally, we identified EGF signaling as a key activator of chondrocyte proliferation. CONCLUSIONS: Osteoarthritic synovial fluid promoted chondrocyte fibrosis and proliferation through EGF receptor activation and downstream MAPK and RhoGTPase signaling.

Risk factors for total ankle arthroplasty failure: A Dutch Arthroplasty Register study.

BACKGROUND: Studies concerning total ankle arthroplasty could be influenced by several forms of bias. Independent national arthroplasty registries represent objective data on survival and patient reported outcomes. The aim of this study was to determine survival and identify risk factors for early failure in a nationwide series of total ankle arthroplasties from the Dutch Arthroplasty Register (LROI). PATIENTS AND METHODS: Data of 810 patients, who received 836 total ankle arthroplasties between 2014 and 2020 were obtained from the Dutch Arthroplasty Register (LROI) with a median follow-up of 38 months (range 1-84 months). Survival was expressed in Kaplan-Meier analysis and associated hazard ratios for implant failure were determined. Implant failure was defined as the need for revision surgery for any reason or (pan)arthrodesis. RESULTS: During follow-up, we recorded 39 failures (4.7%) resulting in a implant survival of 95.3% with a median follow-up of 38 months (range 1-84 months). Medial malleolus osteotomy (HR = 2.27), previous surgery (HR = 1.83), previous osteotomy (HR = 2.82) and previous ligament reconstruction (HR = 2.83) all showed potentially clinically meaningful associations with a higher incidence of implant failure, yet only previous OCD treatment (HR = 6.21), BMI (HR = 1.09) and age (HR = 0.71) were statistically significant. INTERPRETATION: Excellent short-term survival (95.3%) with a median follow-up of 38 months was reported for TAA patients from the Dutch Arthroplasty Register. Patients with a lower age, a higher BMI or who had a prior surgical OCD treatment before TAA surgery appear to have a higher risk for revision after short-term clinical follow-up. Thorough patient selection with emphasis on risk factors associated with early implant failure might be essential to improve TAA survivorship.

Identification of tissue-dependent proteins in knee OA synovial fluid.

OBJECTIVE: For many proteins from osteoarthritic synovial fluid, their intra-articular tissue of origin remains unknown. In this study we performed comparative proteomics to identify osteoarthritis-specific and joint tissue-dependent secreted proteins that may serve as candidates for osteoarthritis biomarker development on a tissue-specific basis. DESIGN: Protein secretomes of cartilage, synovium, Hoffa's fat pad and meniscus from knee osteoarthritis patients were determined using liquid chromatography tandem mass spectrometry, followed by label-free quantification. Validation of tissue-dependent protein species was conducted by ELISA on independent samples. Differential proteomes of osteoarthritic and non-osteoarthritic knee synovial fluids were obtained via similar proteomics approach, followed by ELISA validation. RESULTS: Proteomics revealed 64 proteins highly secreted from cartilage, 94 from synovium, 37 from Hoffa's fat pad and 21 from meniscus. Proteomic analyses of osteoarthritic vs non-osteoarthritic knee synovial fluid revealed 70 proteins with a relatively higher abundance and 264 proteins with a relatively lower abundance in osteoarthritic synovial fluid. Of the 70 higher abundance proteins, 23 were amongst the most highly expressed in the secretomes of a specific intra-articular tissue measured. Tissue-dependent release was validated for SLPI, C8, CLU, FN1, RARRES2, MATN3, MMP3 and TNC. Abundance in synovial fluid of tissue-dependent proteins was validated for IGF2, AHSG, FN1, CFB, KNG and C8. CONCLUSIONS: We identified proteins with a tissue-dependent release from intra-articular human knee OA tissues. A number of these proteins also had an osteoarthritis-specific abundance in knee synovial fluid. These proteins may serve as novel candidates for osteoarthritis biomarker development on a tissue-specific basis.

Hip protectors are cost-effective in the prevention of hip fractures in patients with high fracture risk.

Cost-effective preventive interventions are necessary for tackling the increasing number of hip fractures, which are frequently occuring as a serious consequence of osteoporosis. Several interventions have been available for preventing and treating osteoporosis. The aim of this study was to systematically review and critically appraise studies that assessed cost-effectiveness of hip protectors for the prevention of hip fractures and to investigate the effects of age, gender and residence situation on cost-effectiveness. A systematic review was conducted in order to identify economic evaluation studies examining the hip protector solely or compared to no treatment according to the Preferred Reported Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Synthesis of results was performed to observe trends between the studies. Methodological quality of the studies was assessed by the use of the Quality of Health Economic Studies (QHES) instrument. A total of 15 economic evaluation studies were included for analysis. The methodological quality was high in most studies (13/15). The hip protector was solely evaluated in three studies and within 12 other studies compared with no intervention. All studies that investigated the cost-effectiveness in long-term care facilities revealed that hip protector use is a cost-effective strategy for the prevention of hip fractures in elderly. Cost-effectiveness was also observed in two studies that provided hip protectors in a geriatric hospital ward. Four studies included both community-dwelling residents and residents living in a long-term care facility in their study. These studies showed more variability regarding cost-effectiveness. One study did not report information regarding the residence situation of their cohort, but also observed cost-effectiveness. In conclusion, this review suggests that hip protectors are a cost-effective approach in the prevention of hip fractures in populations with high risk of hip fractures especially in long-term care facilities and a geriatric ward in a hospital.

Percutaneous cement augmentation in the treatment of osteoporotic vertebral fractures (OVFs) in the elderly: a systematic review.

PURPOSE: A systematic review, to study treatment effects for osteoporotic vertebral fractures (OVFs) in the elderly including all available evidence from controlled trials on percutaneous cement augmentation. METHODS: Primary studies, published up to December, 2019, were searched in PubMed and the Cochrane Library. Selected were all prospective controlled studies including patients > 65 years of age and reporting on at least one main outcome. Main outcomes were pain, disability and quality of life (QOL) 1 day post-intervention and at 6 months postoperatively. Excluded were meta-analyses or reviews, retrospective or non-controlled studies, case studies, patients' groups with neoplastic and/or traumatic fractures and/or neurologically compromised patients. RESULTS: Eighteen studies comprising 2165 patients (n = 1117 percutaneous cement augmentation, n = 800 conservative treatment (CT), n = 248 placebo) with a mean follow-up of up to 12 months were included. Pooled results showed significant pain relief in favor of percutaneous cement augmentation compared to CT, direct postoperative and at 6 months follow-up. At 6 months, a significant difference was observed for functional disability scores in favor of percutaneous cement augmentation. When comparing percutaneous cement augmentation to placebo, no significant differences were observed. CONCLUSION: This review incorporates all current available evidence (RCTs and non-RCTs) on the efficacy of percutaneous cement augmentation in the treatment of OVFs in the elderly. Despite methodological heterogeneity of the included studies, this review shows overall significant sustained pain relief and superior functional effect in the short- and long term for percutaneous cement augmentation compared to conservative treatment. These slides can be retrieved under Electronic Supplementary Material.

Long-term clinical outcome of two revision strategies for failed total disc replacements.

PURPOSE: To compare the long-term clinical results and complications of two revision strategies for patients with failed total disc replacements (TDRs). METHODS: In 19 patients, the TDR was removed and the intervertebral defect was filled with a femoral head bone strut graft. In addition, instrumented posterolateral fusion was performed (removal group). In 36 patients, only a posterolateral instrumented fusion was performed (fusion group). Visual Analogue Scale (VAS) for pain and Oswestry Disability Index (ODI) were completed pre- and post-revision surgery. Intra- and post-operative complications of both revision strategies were assessed. RESULTS: The median follow-up was 12.3 years (range 5.3-24.3). In both the removal and fusion groups, a similar (p = 0.515 and p = 0419, respectively) but significant decrease in VAS (p = 0.001 and p = 0.001, respectively) and ODI score (p = 0.033 and p = 0.013, respectively) at post-revision surgery compared to pre-revision surgery was seen. A clinically relevant improvement in VAS and ODI score was found in 62.5% and 43.8% in the removal group and in 43.5% and 39.1% in the fusion group (p = 0.242 and p = 0.773, respectively). Removal of the TDR was associated with substantial intra-operative complications such as major vessel bleeding and ureter lesion. The percentage of late re-operations for complications such as pseudarthrosis were comparable for both revision strategies. CONCLUSIONS: Revision of a failed TDR is clinically beneficial in about half of the patients. No clear benefits for additional TDR removal as compared to posterolateral instrumented fusion alone could be identified. In particular, when considering the substantial risks and complications, great caution is warranted with removal of the TDR. These slides can be retrieved under Electronic Supplementary Material.

Long-term clinical outcome of the Charité III total lumbar disc replacement.

PURPOSE: To compare the long-term clinical results and complications of two revision strategies for patients with failed total disc replacements (TDRs). METHODS: In 19 patients, the TDR was removed and the intervertebral defect was filled with a femoral head bone strut graft. In addition, instrumented posterolateral fusion was performed (removal group). In 36 patients, only a posterolateral instrumented fusion was performed (fusion group). Visual analogue scale (VAS) for pain and Oswestry Disability Index (ODI) were completed pre- and post-revision surgery. Intra- and post-operative complications of both revision strategies were assessed. RESULTS: The median follow-up was 12.3 years (range 5.3-24.3). In both the removal and fusion group, a similar (p = 0.515 and p = 0419, respectively) but significant decrease in VAS- (p = 0.001 and p = 0.001, respectively) and ODI-score (p = 0.033 and p = 0.013, respectively) at post-revision surgery compared to pre-revision surgery was seen. A clinically relevant improvement in VAS- and ODI-score was found in 62.5% and 43.8% in the removal group and in 43.5% and 39.1% in the fusion group (p = 0.242 and p = 0.773, respectively). Removal of the TDR was associated with substantial intra-operative complications such as major vessel bleeding and ureter lesion. The percentage of late reoperations for complications such as pseudarthrosis was comparable for both revision strategies. CONCLUSIONS: Revision of a failed TDR is clinically beneficial in about half of the patients. No clear benefits for additional TDR removal as compared to posterolateral instrumented fusion alone could be identified. Particularly, when considering the substantial risks and complications, great caution is warranted with removal of the TDR. These slides can be retrieved under Electronic Supplementary Material.

Subsidence after total lumbar disc replacement is predictable and related to clinical outcome.

PURPOSE: As yet, there are no studies describing a relationship between radiographic subsidence after lumbar total disc replacement (TDR) and patient symptoms. To investigate if subsidence, in terms of penetrated bone volume or angular rotation over time (ΔPBV and ΔAR), is related to clinical outcome. To assess if subsidence can be predicted by position implant asymmetry (IA) or relative size of the TDR, areal undersizing index (AUI) on direct post-operative radiographs. METHODS: Retrospective cohort study consists of 209 consecutive patients with lumbar TDR for degenerative disc disease. A three-dimensional graphical representation of the implant in relation to the bony endplates was created on conventional radiographs. Consequently, the PBV, AR, IA and AUI were calculated, direct post-operative (DPO) and at last follow-up (LFU). For clinical evaluation, patients with substantial pain (VAS ≥ 50) and malfunction (ODI ≥ 40) were considered failures. RESULTS: At a mean follow-up of 16.7 years, 152 patients (73%) were available for analysis. In 32 patients, revision by spinal fusion had been performed. Both ΔAR (4.33° vs. 1.83°, p = 0.019) and ΔPBV (1448.4 mm3 vs. 747.3 mm3, p = 0.003) were significantly higher in the failure-compared to the success-group. Using ROC curves, thresholds for symptomatic subsidence were defined as ΔPBV ≥ 829 mm3 or PBV-LFU ≥ 1223 mm3 [area under the curve (AUC) 0.723, p = 0.003 and 0.724, p = 0.005, respectively]. Associations between symptomatic subsidence and AUI-DPO ≥ 0.50 (AUC 0.750, p = 0.002) and AR-DPO ≥ 3.95° (AUC 0.690, p = 0.022) were found. CONCLUSION: Subsidence of a TDR is associated with a worse clinical outcome. The occurrence of subsidence is higher in case of incorrect placement or shape mismatch.

Celecoxib-mediated reduction of prostanoid release in Hoffa's fat pad from donors with cartilage pathology results in an attenuated inflammatory phenotype.

OBJECTIVE: The Hoffa's fat pad (HFP) is an intra-articular adipose tissue which is situated under and behind the patella. It contains immune cells next to adipocytes and secretes inflammatory factors during osteoarthritis (OA). In this study, we compared the release profile of prostanoids, which are involved in inflammation, of HFP from OA patients vs patients with a focal cartilage defect (CD) without evidence for OA on MRI and investigated the prostanoid modulatory anti-inflammatory action of celecoxib on HFP. DESIGN: Prostanoid release was analyzed in conditioned medium of HFP explant cultures from 17 osteoarthritic patients and 12 CD patients, in the presence or absence of celecoxib. Furthermore, gene expression of COX enzymes and expression of genes indicative of a pro-inflammatory or anti-inflammatory phenotype of HFP was analyzed. RESULTS: Prostanoid release by HFP from knee OA patients clustered in two subgroups with high and low prostanoid producers. HFP from high prostanoid producers released higher amounts of PGE2, PGF2α and PGD2 compared to HFP from CD patients. PGE2 release by OA HFP was positively associated with expression of genes known to be expressed by M1 macrophages, indicating a role for macrophages. Celecoxib modulated prostanoid release by HFP, and also modulated the inflammation ratio towards a more favorable anti-inflammatory M2 phenotype, most effectively in patients with higher prostanoid release profiles. CONCLUSION: In knee OA patients with inflamed HFP's, celecoxib may exert positive effects in the knee joint via decreasing the release of prostanoids produced by the HFP and by favorably modulating the anti-inflammatory marker expression in HFP.

Impairment of the chondrogenic phase of endochondral ossification in vivo by inhibition of cyclooxygenase-2.

Many studies have reported on the effects of cyclooxygenase-2 (COX-2) inhibition on osteogenesis. However, far less is known about the effects of COX-2 inhibition on chondrogenic differentiation. Previous studies conducted by our group show that COX-2 inhibition influences in vitro chondrogenic differentiation. Importantly, this might have consequences on endochondral ossification processes occurring in vivo, such as bone fracture healing, growth plate development and ectopic generation of cartilage. The goal of our study was to investigate, in vivo, the effect of COX-2 inhibition by celecoxib on the cartilaginous phase of three different endochondral ossification scenarios. 10 mg/kg/day celecoxib or placebo were orally administered for 25 d to skeletally-immature New Zealand White rabbits (n = 6 per group). Endochondral ossification during fracture healing of a non-critical size defect in the ulna, femoral growth plate and ectopically-induced cartilaginous tissue were examined by radiography, micro-computed tomography (µ-CT), histology and gene expression analysis. Celecoxib treatment resulted in delayed bone fracture healing, alterations in growth plate development and progression of mineralisation. In addition, chondrogenic differentiation of ectopically-induced cartilaginous tissue was severely impaired by celecoxib. In conclusion, we found that celecoxib impaired the chondrogenic phase of endochondral ossification.

W/M serrated osteotomy for infantile Blount's disease in Ghana: Short-term results.

PURPOSE: The W/M serrated high tibial osteotomy is a not frequently described surgical technique for simultaneously correcting the varus and torsional deformity in patients with Blount's disease. Without the need for internal fixation, this surgical treatment is well suited for developing countries. This study describes the short-term results of the bilateral and unilateral W/M serrated osteotomy in patients with infantile Blount's disease. METHODS: Between May 2008 and January 2013, 52 patients were treated with uni- (n = 22) or bi-lateral (n = 30) W/M serrated osteotomy of the proximal tibia due to a tibial varus deformity in two district hospitals in Ghana. Other causes than infantile Blount's disease were excluded from the analysis. Pre- and post-operative clinical and radiological measurements were done, and complications were monitored up to 12 weeks after surgery. RESULTS: Seventeen patients (five males, 12 females; mean age 4.9 [standard deviation: 2.10]) were included, which underwent a total of 25 W/M serrated osteotomies. The femorotibial angle was corrected from 34.1° ([mean] range: 6-68°) to - 7.1° ([mean] range: -28-5°). Only one patient had developed a wound infection, and all reached full consolidation. CONCLUSIONS: The W/M serrated osteotomy seems a profitable alternative technique for treating the varus and torsional deformity in patients with Blount's disease in the circumstances of developing countries. The short-term outcomes are good and promising with a low complication rate and good consolidation. Long-term follow-up results of these patients are needed to observe possible complications. LEVEL OF EVIDENCE: IV, therapeutic case series.

Identification of Predictors for Progression of Scoliosis in Rett Syndrome.

Rett syndrome is a neurodevelopmental disorder in which scoliosis is a common orthopedic complication. This explorative study aims to identify predictors for rapid progression of scoliosis in Rett syndrome to enable variable selection for future prediction model development. A univariable logistic regression model was used to identify variables that discriminate between individuals with and without rapid progression of scoliosis (>10 ∘Cobb angle/6 months) based on multi-center data. Predictors were identified using univariable logistic regression with OR (95% CI) and AUC (95% CI). Age at inclusion, Cobb angle at baseline and epilepsy have the highest discriminative ability for rapid progression of scoliosis in Rett syndrome.

Triple red blood cell alloantibody formation after bone-allograft transplantation.

In this case report, we provide evidence for the possibility of red blood cell alloimmunization after bone-allograft transplantation. Here, we present a 13-year-old boy who received a bone allograft due to impending hip-luxation. Five months later he was shown to have developed three different alloantibodies: anti-D, anti-C and anti-E, which were induced by the bone allograft. Red blood cell alloimmunization is a possible adverse event when a patient is exposed to allogenic red blood cells. These antibodies may cause transfusion reactions when incompatible blood is administered. More importantly, these antibodies may cause severe, or even fatal, hemolytic disease of the fetus or newborn, stretching the importance of preventing antibody formation, especially in young women. This case demonstrates the importance of selecting rhesus phenotype compatible bone allografts.

Hypertrophic differentiation during chondrogenic differentiation of progenitor cells is stimulated by BMP-2 but suppressed by BMP-7.

OBJECTIVE: Bone morphogenic protein (BMP)-2 and BMP-7 are clinically approved and their recombinant proteins are used for bone tissue regenerative purposes and widely evaluated for cartilage regeneration. Previous comparison of the in vitro chondrogenic characteristics of BMP-2 vs BMP-7 did not address hypertrophic differentiation and characterizing their chondrogenic properties with a focus in on chondrocyte hypertrophy was topic of investigation in this study. DESIGN: Equimolar concentrations of BMP-2 or BMP-7 were added to chondrogenic differentiating ATDC5, human bone marrow stem cells or rabbit periosteal explants. Expression of Col2a1, Sox9, Acan, Col10a1, Runx2, ALP, Mmp13, Mef2c and Bapx1/Nkx3.2 was determined by reverse transcription-quantitative PCR (RT-qPCR) and immunoblotting. Glycosaminoglycan content, cell proliferation capacity and ALP activity were analysed by colourimetric analyses. Expression of Bapx1/Nkx3.2 and Sox9 was targeted by transfection of target specific siRNA duplexes. RESULTS: BMP-2 dose-dependently increased chondrocyte hypertrophy during chondrogenic differentiation of progenitor cells, whereas BMP-7 acted hypertrophy-suppressive and chondro-promotive. Both BMPs did not influence cell proliferation, but they did increase total glycosaminoglycan content. In a candidate approach Bapx1/Nkx3.2 was found to be involved in the BMP-7 mediated suppression of chondrocyte hypertrophy in ATDC5 cells. CONCLUSIONS: BMP-2 and BMP-7 display opposing actions on the chondrogenic outcome of differentiating progenitor cells: BMP-2 acts a specific inducer of chondrocyte hypertrophy, while BMP-7 appears to increase or maintain chondrogenic potential and prevent chondrocyte hypertrophy. Our results pave the way for an application-dependent differential use of BMP-2 or BMP-7.

Sprengel's deformity and spinal dysraphism: connecting the shoulder and the spine.

BACKGROUND AND PURPOSE: Sprengel's deformity, a rare congenital malformation of the scapula, may be observed in combination with spinal dysraphism. The co-occurrence of these malformations suggests an unknown shared etiology. Therefore, we reviewed the medical records of eight children presenting with both malformations and performed a review of the literature. PATIENTS AND METHODS: Databases from four university medical centers were searched for children presenting between 1992 and 2012 with spinal dysraphism and a Sprengel's deformity. CONCLUSION: The combination of spinal dysraphism and Sprengel's deformity is rare, and is associated with segmentation defects of the spine and ribs. Although the etiology of both spinal dysraphism and Sprengel's deformity remains unclear, all deformities of the spine, ribs, and shoulder might result from a common genetic defect affecting somitogenesis.