van Wijnen, Andre J

Background: The preoperative assessment of cartilage lesions is critical to surgical planning and decision making. The accurate radiographic determination of acetabular cartilage damage has remained elusive for modern imaging modalities, including magnetic resonance imaging (MRI) and magnetic resonance arthrography (MRA). While risk factors have been individually described, no multivariable system exists for predicting high-grade cartilage damage. Purpose: To determine the preoperative predictors of grade 3 to 4 acetabular labrum articular disruption (ALAD) lesions. Study Design: Case-control study; Level of evidence, 3. Cohort study (diagnosis); Level of evidence, 1. Methods: Retrievable radiographs were reviewed from primary hip arthroscopic procedures performed at 2 high-volume institutions between December 2007 and April 2017. The predictive value of demographic and radiographic factors for the intraoperative documentation of ALAD grade 3 to 4 damage was analyzed and entered into a multivariable model, and a statistically guided scoring system for the damage risk was created using the Akaike information criterion. The scoring system was then prospectively validated on 167 patients who underwent primary hip arthroscopy between April 2017 and February 2018. Results: A total of 652 primary hip arthroscopic procedures in 614 patients (390 female, 224 male; mean age, 33.2 ± 12.5 years; mean body mass index, 26.9 ± 5.5 kg/m 2 ) from 2007 to 2017 were analyzed. Male sex (odds ratio [OR], 3.11; P < .01), age ≥35 years (OR, 1.96; P < .01), cam morphology (alpha angle >55°) (OR, 2.96; P < .01), and Tönnis grade 1 to 2 (grade 1: OR, 4.14; P < .01, and grade 2: OR, 9.29; P < .01) were univariate risk factors for intraoperatively documented high-grade damage. A multivariable scoring system, the Rapidly Assessed Predictor of Intraoperative Damage (RAPID) score (0-5 points), was generated based on sex, Tönnis grade, and cam morphology. Patients with increasing RAPID scores had an increasing risk of damage, with a 10.5% risk for those with 0 points and an 88.0% risk for those with 5 points ( P < .01). The area under the curve was 0.75 for the study group and 0.76 for the validation group ( P = .94). Conclusion: While preoperative MRI has diagnostic value for hip arthroscopic surgery, the RAPID score provides added benefit as a readily employable, in-clinic system for predicting high-grade cartilage damage. The discriminatory value of the RAPID score compares favorably with previous MRI and MRA studies. This information will help the clinician and patient plan for high-grade damage and identify potential targets for cartilage treatment.

Background Twelve paired fresh frozen cadaveric wrists were randomized to a 360-degree tenodesis repair group or the 360-degree tenodesis repair with an internal brace (suture tape) construct. Case Description The specimens were preloaded to 5 N and subsequently biomechanically loaded to failure, at a rate of 0.1 mm/s on a jig that allowed for axial load. The maximum load and mode of failure were recorded. Load to failure in the 360 tenodesis group with internal brace was 283.47 ± 100.25 N, compared with the 360 tenodesis group only, whose yield strength was 143.61 ± 90.54 N. The mode of failure within the internal brace construct was either through knot slippage, graft disruption, or bone separation from strength testing construct. The 360 tenodesis group tended to fail via graft slippage or graft rupture. Literature Review The management of scapholunate instability can be a difficult problem to treat. Traditionally, many of the surgical reconstructions have focused upon dorsal ligament reconstruction with Kirschner (K) wire fixation. This results in prolonged immobilization of the wrist with varied outcomes, in part due to the multiaxial instability that may persist due to concomitant volar ligament disruption. To address this instability, surgical techniques have been devised that address both the volar and dorsal ligament injuries. Clinical Relevance Scapholunate reconstruction with a 360-degree tenodesis and internal brace augmentation (SLITT procedure) provided superior biomechanical stability than tenodesis alone.

Abstract Expression of Runx2/p57 is a hallmark of the osteoblast‐lineage identity. Although several regulators that control the expression of Runx2/p57 during osteoblast‐lineage commitment have been identified, the epigenetic mechanisms that sustain this expression in differentiated osteoblasts remain to be completely determined. Here, we assess epigenetic mechanisms associated with Runx2/p57 gene transcription in differentiating MC3T3 mouse osteoblasts. Our results show that an enrichment of activating histone marks at the Runx2/p57 P1 promoter is accompanied by the simultaneous interaction of Wdr5 and Utx proteins, both are components of COMPASS complexes. Knockdown of Wdr5 and Utx expression confirms the activating role of both proteins at the Runx2‐P1 promoter. Other chromatin modifiers that were previously described to regulate Runx2/p57 transcription in mesenchymal precursor cells (Ezh2, Prmt5, and Jarid1b proteins) were not found to contribute to Runx2/p57 transcription in full‐committed osteoblasts. We also determined the presence of additional components of COMPASS complexes at the Runx2/p57 promoter, evidencing that the Mll2/COMPASS‐ and Mll3/COMPASS‐like complexes bind to the P1 promoter in osteoblastic cells expressing Runx2/p57 to modulate the H3K4me1 to H3K4me3 transition.

Mesenchymal stem cells (MSCs) constitute an important repair system, but may be impaired by exposure to cardiovascular risk factors. Consequently, adipose tissue-derived MSCs from pigs with the metabolic syndrome (MetS) show decreased vitality. A growing number of microRNAs (miRNAs) are recognized as key modulators of senescence, but their role in regulating senescence in MSC in MetS is unclear. We tested the hypothesis that MetS upregulates in MSC expression of miRNAs that can serve as post-transcriptional regulators of senescence-associated (SA) genes. MSCs were collected from swine abdominal adipose tissue after 16 weeks of Lean or Obese diet ( n = 6 each). Next-generation miRNA sequencing (miRNA-seq) was performed to identify miRNAs up-or down-regulated in MetS-MSCs compared with Lean-MSCs. Functional pathways of SA genes targeted by miRNAs were analyzed using gene ontology. MSC senescence was evaluated by p16 and p21 immunoreactivity, H2AX protein expression, and SA-β-Galactosidase activity. In addition, gene expression of p16, p21, MAPK3 (ERK1) and MAPK14, and MSC migration were studied after inhibition of SA-miR-27b. Senescence biomarkers were significantly elevated in MetS-MSCs. We found seven upregulated miRNAs, including miR-27b, and three downregulated miRNAs in MetS-MSCs, which regulate 35 SA genes, particularly MAPK signaling. Inhibition of miR-27b in cultured MSCs downregulated p16 and MARP3 genes, and increased MSC migration. MetS modulates MSC expression of SA-miRNAs that may regulate their senescence, and the p16 pathway seems to play an important role in MetS-induced MSC senescence.

Aims Dupuytren’s contracture is a benign, myoproliferative condition affecting the palmar fascia that results in progressive contractures of the fingers. Despite increased knowledge of the cellular and connective tissue changes involved, neither a cure nor an optimum form of treatment exists. The aim of this systematic review was to summarize the best available evidence on the management of this condition. Materials and Methods A comprehensive database search for randomized controlled trials (RCTs) was performed until August 2017. We studied RCTs comparing open fasciectomy with percutaneous needle aponeurotomy (PNA), collagenase clostridium histolyticum (CCH) with placebo, and CCH with PNA, in addition to adjuvant treatments aiming to improve the outcome of open fasciectomy. A total of 20 studies, involving 1584 patients, were included. Results PNA tended to provide higher patient satisfaction with fewer adverse events, but had a higher rate of recurrence compared with limited fasciectomy. Although efficacious, treatment with CCH had notable recurrence rates and a high rate of transient adverse events. Recent comparative studies have shown no difference in clinical outcome between patients treated with PNA and those treated with CCH. Conclusion Currently there remains limited evidence to guide the management of patients with Dupuytren’s contracture. Cite this article: Bone Joint J 2018;100-B:1138–45.

Abstract The endosteal niche is a component of the bone marrow microenvironment that can serve to protect hematological malignancies such as acute myeloid leukemia (AML) from standard chemotherapies such as cytarabine (Ara-C). Surviving AML cells harbored by this niche can eventually lead to relapse. The endosteal niche is rich in osteoblast lineage cells. U937 or KG1a AML cell lines were cultured with or without osteoblast lineage cells (MC3T3 or W-20-17 cell lines), challenged with doses of 0µM, 0.1µM, 0.5µM, 1µM, 5µM, or 10µM of Ara-C, and assayed for apoptosis via annexin-V staining and flow cytometry. Osteoblast lineage cells (MC3T3 or W-20-17 cell lines) were able to protect AML cells (U937 or KG1a cell lines) from Ara-C-induced apoptosis. Histone deacetylase inhibitors (HDACi) globally alter gene expression within cells. When we pre-treated osteoblast lineage cells (MC3T3) with the HDACi vorinostat (suberoylanilide hydroxamic acid, SAHA), it reduced the ability of the osteoblast lineage cells (MC3T3) to protect AML cells (U937) from Ara-C-induced apoptosis, which we have previously confirmed in the KG1a AML cell line as well. This indicates that osteoblast lineage cell-mediated protection of AML from Ara-C occurs via an HDACi sensitive mechanism. To begin to further explore the mechanism of action, we co-cultured AML cells (KG1a or U937) with and without osteoblast lineage cells (MC3T3) in the presence or absence of a transwell. We found that the presence of the transwell reduced the osteoblast lineage cell-mediated protection, indicating that osteoblast lineage cell-mediated protection of AML from Ara-C is cell contact dependent. Thus, osteoblast lineage cells can protect AML cells from Ara-C induced apoptosis, this protection can be reduced by pre-treatment of the osteoblast lineage cells with the HDACi vorinostat, and osteoblast lineage cell-mediated protection from Ara-C is cell contact dependent. These studies begin to characterize the mechanisms of osteoblast lineage cell-mediated protection of AML from Ara-C. Manipulating the protective properties of osteoblast lineage cells of the endosteal niche may help make AML cells more susceptible to chemotherapeutics. Therefore, developing combination therapies that target the protective mechanisms of osteoblast-lineage cells may help to further deplete the bone marrow microenvironment of AML cells and prevent relapse of disease. Citation Format: Rosalie M. Sterner, Kimberly N. Kremer, Meagan R. Rollins, Amel Dudakovic, Jennifer J. Westendorf, Andre J. van Wijnen, Karen E. Hedin. Osteoblast-lineage cells protect AML cells from cytarabine-induced apoptosis via a mechanism sensitive to HDACi and reduced cell-cell contact [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2137.

Breast cancer is the most common cancer in women, and accounts for ~30% of new cancer cases and 15% of cancer‐related deaths. Tumor relapse and metastasis are primary factors contributing to breast cancer‐related deaths. Therefore, the challenge for breast cancer treatment is to sustain remission. A driving force behind tumor relapse is breast cancer heterogeneity (both intertumor, between different patients, and intratumor, within the same tumor). Understanding breast cancer heterogeneity is necessary to develop preventive interventions and targeted therapies. A recently emerging concept is that intratumor heterogeneity is driven by cancer stem cells (CSCs) that are capable of giving rise to a multitude of different cells within a tumor. Studies have highlighted linkage of CSC formation with epithelial‐to‐mesenchymal transition (EMT). In this review, we summarize the current understanding of breast cancer heterogeneity, links between EMT and CSCs, regulation of EMT by Runx transcription factors, and potential therapeutic strategies targeting these processes.

Background: Extracellular vesicles (EVs) released from mesenchymal stem/stromal cells (MSCs) mediate their paracrine effect, but their efficacy to protect the microcirculation of the kidney is unknown. Using a novel swine model of unilateral renovascular disease (RVD) complicated by metabolic syndrome (MetS), we tested the hypothesis that EVs would attenuate renal microvascular loss. Methods: Four groups of pigs ( n = 7 each) were studied after 16 weeks of diet-induced MetS and RVD (MetS+RVD), MetS+RVD treated 4 weeks earlier with a single intra-renal delivery of EVs harvested from autologous adipose tissue-derived MSCs, and Lean and MetS Sham controls. Stenotic-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were measured in-vivo (fast CT), whereas EV characteristics, renal microvascular architecture (micro-CT), and injury pathways were studied ex-vivo. Results: mRNA sequencing and proteomic analysis revealed that EVs are packed with several pro-angiogenic genes and proteins, such as vascular endothelial growth factor. Labeled EVs were detected in the stenotic kidney 4 weeks after injection internalized by tubular and endothelial cells. EVs restored renal expression of angiogenic factors and improved cortical microvascular and peritubular capillary density. Renal apoptosis, oxidative stress, tubular injury, and fibrosis were also attenuated in EV-treated pigs. RBF and GFR decreased in MetS+RVD compared with MetS, but normalized in MetS+RVD+EVs. Conclusions: Intra-renal delivery of MSC-derived EVs bearing pro-angiogenic properties restored the renal microcirculation and in turn hemodynamics and function in chronic experimental MetS+RVD. Our study suggests a novel therapeutic potential for MSC-derived EVs in restoring renal hemodynamics in experimental MetS+RVD.

Elevated levels of follistatin‐like protein 1 (FSTL1) have been found both in mouse models for human rheumatoid arthritis (RA) and collagen‐induced arthritis (CIA). In this study, we elucidated the potential mechanisms by which FSTL1 contributes to the pathogenesis of RA. Fibroblast‐like synoviocytes (FLSs) were established from synovial tissues of RA patients and stimulated with human recombinant FSTL1. Protein and mRNA expression levels of select matrix metalloproteinases (i.e., MMP1, MMP3, MMP13) in FLS were measured by, respectively, real‐time RT‐qPCR and ELISA. Activation of MAPK and other pathways that affect MMPs were evaluated by Western blotting. We also compared concentrations of MMPs in plasma in RA patients versus healthy controls (HC). Expression levels of MMP1, MMP3, and MMP13 were clearly stimulated by FSTL1 in vitro. FSTL1 activated the inflammation‐related NF‐κB signaling pathway, as well as all three mitogen‐activated protein kinase (MAPK) pathways and the JAK/STAT3 pathway. Moreover, select chemical inhibitors that target p38 (SB203580), Erk1/2 (SP600125), JNK (SCH772984), STAT3 (AG490), and NF‐κB (BAY 11–7082) significantly attenuated MMP expression. Inhibition of Toll‐like receptor 4 by compound TAK‐242 significantly abolished those effects of FSTL1. Importantly, elevated plasma concentrations of MMP3 were found to correlate with plasma FSTL1 levels in RA patients. These findings suggest that FSTL1 accelerates RA progression by activating MAPK, JAK/STAT3, and NF‐κB pathways to enhance secretion of different MMPs and this enhancement is via TLR4. Targeting FSTL1 may provide a promising pharmacological drug therapy to ameliorate RA symptoms and perhaps reverse disease progression.