The PIKASO trial (Preventing Injured Knees from Osteoarthritis: Severity Outcomes): Rationale and design features for a randomized controlled trial.

Objective: Given the high burden and increasing prevalence of post-traumatic osteoarthritis (PTOA), identifying clinically beneficial strategies to prevent or delay its onset could improve the quality of life of those at high risk of developing the disease.

Methods: Preventing Injured Knees from OsteoArthritis: Severity Outcomes (PIKASO) is a multicenter blinded, parallel, two-arm randomized controlled trial of 512 individuals aged 18-45 years undergoing anterior cruciate ligament reconstruction (ACLR). This study is designed to evaluate the efficacy of a 12-month intervention of oral metformin vs.

vSPACE: exploring virtual spatial representation of articular chondrocytes at the single-cell level.

Summary: vSPACE is a web-based application presenting a spatial representation of scRNAseq data obtained from human articular cartilage by emulating the concept of spatial transcriptomics technology, but virtually. This virtual 2D plot presentation of human articular cartage cells generates several zonal distribution patterns, for one or multiple genes at a time, revealing patterns that scientists can appreciate as imputed spatial distribution patterns along the zonal axis.

Availability And Implementation: vSPACE is implemented in Python Dash as a web-based toolbox designed for data visualization of zonal gene expression patterns in articular cartilage chondrocytes.

Clinical and biobehavioral phenotypic assessments and data harmonization for the RE-JOIN research consortium: Recommendations for common data element selection.

Background: The Restoring Joint Health and Function to Reduce Pain (RE-JOIN) Consortium is part of the Helping to End Addiction Long-term® (HEAL) Initiative. HEAL is an ambitious, NIH-wide initiative to speed scientific solutions to stem the national opioid public health crisis. The RE-JOIN consortium's over-arching goal is to define how chronic joint pain-mediating neurons innervate different articular and -articular tissues, with a focus on the knee and temporomandibular joints (TMJ) across species employing the latest neuroscience approaches.

Shared and Compartment-Specific Processes in Nucleus Pulposus and Annulus Fibrosus During Intervertebral Disc Degeneration.

Elucidating how cell populations promote onset and progression of intervertebral disc degeneration (IDD) has the potential to enable more precise therapeutic targeting of cells and mechanisms. Single-cell RNA-sequencing (scRNA-seq) is performed on surgically separated annulus fibrosus (AF) (19,978; 26,983 cells) and nucleus pulposus (NP) (20,884; 24,489 cells) from healthy and diseased human intervertebral discs (IVD). In both tissue types, depletion of cell subsets involved in maintenance of healthy IVD is observed, specifically the immature cell subsets - fibroblast progenitors and stem cells - indicative of an impairment of normal tissue self-renewal.

vSPACE: Exploring Virtual Spatial Representation of Articular Chondrocytes at the Single-Cell Level.

Single cell RNA sequencing technology has been dramatically changing how gene expression studies are performed. However, its use has been limited to identifying subtypes of cells by comparing cells' gene expression levels in an unbiased manner to produce a 2D plot (e.g.

New approach to testing treatments for osteoarthritis: FastOA.

Animal models of post traumatic osteoarthritis have shown many promising treatments for disease, but human trials have mostly failed to identify effective treatments. This viewpoint suggests that the frequent failure of drug and treatment development in osteoarthritis is due, in part, to the advanced stage of disease of patients in trials and suggests that mirroring the animal model approach might be more successful. It suggests a path forward by enriching trial enrollees with those likely to develop post traumatic OA quickly.

Mocetinostat activates Krüppel-like factor 4 and protects against tissue destruction and inflammation in osteoarthritis.

Osteoarthritis (OA) is the most common joint disorder, and disease-modifying OA drugs (DMOADs) represent a major need in OA management. Krüppel-like factor 4 (KLF4) is a central transcription factor upregulating regenerative and protective functions in joint tissues. This study was aimed to identify small molecules activating KLF4 expression and to determine functions and mechanisms of the hit compounds.

RNA-binding proteins that are highly expressed and enriched in healthy cartilage but suppressed in osteoarthritis.

RNA-binding proteins (RBPs) have diverse and essential biological functions, but their role in cartilage health and disease is largely unknown. The objectives of this study were (i) map the global landscape of RBPs expressed and enriched in healthy cartilage and dysregulated in osteoarthritis (OA); (ii) prioritize RBPs for their potential role in cartilage and in OA pathogenesis and as therapeutic targets. Our published bulk RNA-sequencing (RNA-seq) data of healthy and OA human cartilage, and a census of 1,542 RBPs were utilized to identify RBPs that are expressed in healthy cartilage and differentially expressed (DE) in OA.

miR-26a deficiency is associated with bone loss and reduced muscle strength but does not affect severity of cartilage damage in osteoarthritis.

Osteoarthritis (OA) is the most common age-related joint disease. However, the role of many microRNAs (miRNA) in skeletal development and OA pathogenesis has not been sufficiently elucidated using genetically modified mice with gain- and loss-of-function models. We generated Cartilage-specific miR-26a overexpressing (Col2a1-Cre;miR-26a Tg: Cart-miR-26a Tg) mice and global miR-26a knockout (miR-26a KO) mice.

Promotion of Joint Degeneration and Chondrocyte Metabolic Dysfunction by Excessive Growth Hormone in Mice.

Objective: Many patients with acromegaly, a hormonal disorder with excessive growth hormone (GH) production, report pain in joints. We undertook this study to characterize the joint pathology of mice with overexpression of bovine GH (bGH) or a GH receptor antagonist (GHa) and to investigate the effect of GH on regulation of chondrocyte cellular metabolism.

Methods: Knee joints from mice overexpressing bGH or GHa and wild-type (WT) control mice were examined using histology and micro-computed tomography for osteoarthritic (OA) pathologies.

miR-23a/b clusters are not essential for the pathogenesis of osteoarthritis in mouse aging and post-traumatic models.

Osteoarthritis (OA), the most prevalent aging-related joint disease, is characterized by insufficient extracellular matrix synthesis and articular cartilage degradation and is caused by various risk factors including aging and traumatic injury. Most microRNAs (miRNAs) have been associated with pathogenesis of osteoarthritis (OA) using models. However, the role of many miRNAs in skeletal development and OA pathogenesis is uncharacterized using genetically modified mice.

Human-specific duplicate CHRFAM7A gene is associated with more severe osteoarthritis and amplifies pain behaviours.

Objectives: CHRFAM7A is a uniquely human fusion gene that functions as a dominant negative regulator of alpha 7 acetylcholine nicotinic receptor (α7nAChR) in vitro. This study determined the impact of CHRFAM7A on α7nAChR agonist responses, osteoarthritis (OA) severity and pain behaviours and investigated mechanisms.

Methods: Transgenic CHRFAM7A (TgCHRFAM7A) mice were used to determine the impact of CHRFAM7A on knee OA histology, pain severity in OA and other pain models, response to nAchR agonist and IL-1β.

Senescent cell population with ZEB1 transcription factor as its main regulator promotes osteoarthritis in cartilage and meniscus.

Objectives: Single-cell level analysis of articular cartilage and meniscus tissues from human healthy and osteoarthritis (OA) knees.

Methods: Single-cell RNA sequencing (scRNA-seq) analyses were performed on articular cartilage and meniscus tissues from healthy (n=6, n=7) and OA (n=6, n=6) knees. Expression of genes of interest was validated using immunohistochemistry and RNA-seq and function was analysed by gene overexpression and depletion.

Promotion of Knee Cartilage Degradation by IκB Kinase ε in the Pathogenesis of Osteoarthritis in Human and Murine Models.

Objective: NF-κB signaling is an important modulator in osteoarthritis (OA), and IκB kinase ε (IKKε) regulates the NF-κB pathway. This study was undertaken to identify the functional involvement of IKKε in the pathogenesis of OA and the effectiveness of IKKε inhibition as a modulatory treatment.

Methods: IKKε expression in normal and OA human knee joints was analyzed immunohistochemically.

Senescence-accelerated mice prone 8 (SAMP8) in male as a spontaneous osteoarthritis model.

Background: Animal models of spontaneous osteoarthritis (OA) are sparse and not well characterized. The purpose of the present study is to examine OA-related changes and mechanisms in senescence-accelerated mouse prone 8 (SAMP8) that displays a phenotype of accelerated aging.  METHODS: Knees of male SAMP8 and SAM-resistant 1 (SAMR1) mice as control from 6 to 33 weeks of age were evaluated by histological grading systems for joint tissues (cartilage, meniscus, synovium, and subchondral bone), and µCT analysis.

Targeting FoxO transcription factors with HDAC inhibitors for the treatment of osteoarthritis.

Objectives: Osteoarthritis (OA) features ageing-related defects in cellular homeostasis mechanisms in articular cartilage. These defects are associated with suppression of forkhead box O (FoxO) transcription factors. FoxO1 or FoxO3 deficient mice show early onset OA while FoxO1 protects against oxidative stress in chondrocytes and promotes expression of autophagy genes and the essential joint lubricant proteoglycan 4 (PRG4).

Urolithin A improves mitochondrial health, reduces cartilage degeneration, and alleviates pain in osteoarthritis.

Osteoarthritis (OA) is the most common age-related joint disorder with no effective therapy. According to the World Health Organization, OA affects over 500 million people and is characterized by degradation of cartilage and other joint tissues, severe pain, and impaired mobility. Mitochondrial dysfunction contributes to OA pathology.

The mechanosensitive ion channel PIEZO1 is expressed in tendons and regulates physical performance.

How mechanical stress affects physical performance via tendons is not fully understood. Piezo1 is a mechanosensitive ion channel, and E756del was recently found as a gain-of-function variant that is common in individuals of African descent. We generated tendon-specific knock-in mice using R2482H , a mouse gain-of-function variant, and found that they had higher jumping abilities and faster running speeds than wild-type or muscle-specific knock-in mice.

Krüppel-like factor-4 and Krüppel-like factor-2 are important regulators of joint tissue cells and protect against tissue destruction and inflammation in osteoarthritis.

Objectives: Analysing expression patterns of Krüppel-like factor (KLF) transcription factors in normal and osteoarthritis (OA) human cartilage, and determining functions and mechanisms of KLF4 and KLF2 in joint homoeostasis and OA pathogenesis.

Methods: Experimental approaches included human joint tissues cells, transgenic mice and mouse OA model with viral KLF4 gene delivery to demonstrate therapeutic benefit in structure and pain improvement. Mechanistic studies applied global gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq).

Guided flapless apicoectomy of the palatal root of a maxillary molar: a case presentation.

This case report presents a novel approach for minimally invasive fully guided apicoectomy of the palatal root of a maxillary first molar using a custom-made 3D-printed template. To date, the development of diagnostic radiographic tools such as high-resolution CBCT devices, as well as of CAD planning software and CAM technologies, like 3D printing, allow for increased application in endodontics. The patient (a 38-year-old woman) suffered from pain on the right side of the face since 4 weeks and was diagnosed with chronic apical periodontitis of the palatal root of the maxillary right first molar.

[Alveolar ridge preservation with autologous dentin following cystectomy].

This case report illustrates a new application of autologous dentin for defect augmentation. After cystectomy of a follicular cyst in the maxilla, autologous particulated dentin from the wisdom tooth is used for augmentation due to periodontal compromise of neighbouring teeth. The combination of simultaneous wisdom tooth removal and augmentation is a convenient option in this case.

Collagen fibrous scaffolds for sustained delivery of growth factors for meniscal tissue engineering.

To mimic the ultrastructural morphology of the meniscus with nanofiber scaffolds coupled with controlled growth factor delivery to modulate cellular performance for tissue engineering of menisci. The authors functionalized collagen nanofibers by conjugating heparin to the following growth factors for sustained release: PDGF-BB, TGF-β1 and CTGF. Incorporating growth factors increased human meniscal and synovial cell viability, proliferation and infiltration , and ; upregulated key genes involved in meniscal extracellular matrix synthesis and enhanced generation of meniscus-like tissue.

Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis.

Osteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes.