Transcript-dependent effects of the CALCA gene on the progression of post-traumatic osteoarthritis in mice.

Osteoarthritis represents a chronic degenerative joint disease with exceptional clinical relevance. Polymorphisms of the CALCA gene, giving rise to either a procalcitonin/calcitonin (PCT/CT) or a calcitonin gene-related peptide alpha (αCGRP) transcript by alternative splicing, were reported to be associated with the development of osteoarthritis. The objective of this study was to investigate the role of both PCT/CT and αCGRP transcripts in a mouse model of post-traumatic osteoarthritis (ptOA). WT, αCGRP-/- and CALCA-/- mice were subjected to anterior cruciate ligament transection (ACLT) to induce ptOA of the knee. Mice were sacrificed 4 and 8 weeks post-surgery, followed by micro-CT and histological evaluation. Here we show that the expression of both PCT/CT and αCGRP transcripts is induced in ptOA knees. CALCA-/- mice show increased cartilage degeneration and subchondral bone loss with elevated osteoclast numbers compared to αCGRP-/- and WT mice. Osteophyte formation is reduced to the same extent in CALCA-/- and αCGRP-/- mice compared to WT controls, while a reduced synovitis score is noticed exclusively in mice lacking CALCA. Our data show that expression of the PCT/CT transcript protects from the progression of ptOA, while αCGRP promotes osteophyte formation, suggesting that CALCA-encoded peptides may represent novel targets for the treatment of ptOA.

Loading of the Hip and Knee During Swimming: An in Vivo Load Study.

BACKGROUND: Swimming is commonly recommended as postoperative rehabilitation following total hip arthroplasty (THA) and total knee arthroplasty (TKA). So far, in vivo hip and knee joint loads during swimming remain undescribed. METHODS: In vivo hip and knee joint loads were measured in 6 patients who underwent THA and 5 patients who underwent TKA with instrumented joint implants. Joint loads, including the resultant joint contact force (F Res ), torsional moment around the femoral shaft axis or the tibial axis (M Tors ), bending moment at the middle of the femoral neck (M Bend ), torsional moment around the femoral neck axis (M Tne ), and medial force ratio (MFR) in the knee, were measured during breaststroke swimming at 0.5, 0.6, and 0.7 m/s and the breaststroke and crawl kicks at 0.5 and 1.0 m/s. RESULTS: The ranges of the median maximal F Res were 157% to 193% of body weight for the hip and 93% to 145% of body weight for the knee during breaststroke swimming. Greater maxima of F Res (hip and knee), M Tors (hip and knee), M Bend (hip), and M Tne (hip) were observed with higher breaststroke swimming velocities, but significance was only identified between 0.5 and 0.6 m/s in F Res (p = 0.028), M Tors (p = 0.028), and M Bend (p = 0.028) and between 0.5 and 0.7 m/s in F Res (p = 0.045) in hips. No difference was found in maximal MFR between different breaststroke swimming velocities. The maximal F Res was significantly positively correlated with the breaststroke swimming velocity (hip: r = 0.541; p < 0.05; and knee: r = 0.414; p < 0.001). The maximal F Res (hip and knee) and moments (hip) were higher in the crawl kick than in the breaststroke kick, and a significant difference was recognized in F Res Max for the hip: median, 179% versus 118% of body weight (p = 0.028) for 0.5 m/s and 166% versus 133% of body weight (p = 0.028) for 1.0 m/s. CONCLUSIONS: Swimming is a safe and low-impact activity, particularly recommended for patients who undergo THA or TKA. Hip and knee joint loads are greater with higher swimming velocities and can be influenced by swimming styles. Nevertheless, concrete suggestions to patients who undergo arthroplasty on swimming should involve individual considerations. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

The dual pro-inflammatory and bone-protective role of calcitonin gene-related peptide alpha in age-related osteoarthritis.

BACKGROUND: The vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigated whether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA. METHODS: Sixteen- to 18-month-old αCGRP-deficient mice (αCGRP-/-aged) were compared to, first, age-matched wild type (WTaged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP-/-CTRL) and non-OA WT animals (WTCTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and µ-computed tomography. RESULTS: WTaged mice exhibited elevated αCGRP serum levels compared to young WTCTRL animals. Marked signs of OA-induced cartilage destruction were seen in WTaged animals, while αCGRP-/-aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WTaged but not in αCGRP-/-aged mice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA. CONCLUSIONS: Similar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.

Nesting behavior is associated with body weight and grip strength loss in mice suffering from experimental arthritis.

Objective animal health evaluation is essential to determine welfare and discomfort in preclinical in vivo research. Body condition scores, body weight, and grimace scales are commonly used to evaluate well-being in murine rheumatoid arthritis (RA) and osteoarthritis experiments. However, nest-building, a natural behavior in mice, has not yet been evaluated in wild type (WT) or genetically modified rodents suffering from collagen antibody-induced arthritis (CAIA). To address this, we analyzed nesting behavior in WT mice, calcitonin gene-related peptide alpha-deficient (αCGRP-/-) mice, and calcitonin receptor-deficient (Calcr-/-) mice suffering from experimental RA compared to healthy control (CTRL) groups of the same genotypes. CAIA was induced in 10-12-week-old male mice, and clinical parameters (body weight, grip strength, clinical arthritis score, ankle size) as well as nesting behavior were assessed over 10 or 48 days. A slight positive association between the nest score and body weight and grip strength was found for animals suffering from CAIA. For the clinical arthritis score and ankle size, no significant associations were observed. Mixed model analyses confirmed these associations. This study demonstrates that clinical effects of RA, such as loss of body weight and grip strength, might negatively affect nesting behavior in mice. Assessing nesting behavior in mice with arthritis could be an additional, non-invasive and thus valuable health parameter in future experiments to monitor welfare and discomfort in mice. During severe disease stages, pre-formed nest-building material may be provided to animals suffering from arthritis.

Restoration of Hip Geometry after Femoral Neck Fracture: A Comparison of the Femoral Neck System (FNS) and the Dynamic Hip Screw (DHS).

BACKGROUND: The femoral neck system (FNS) was introduced as a minimally invasive fixation device for managing femoral neck fractures. OBJECTIVE: To compare radiographic, clinical, and patient-reported outcome measures (PROMs) of femoral neck fracture patients following FNS compared to dynamic hip screw (DHS) implantation combined with an anti-rotational screw. METHODS: Patients who underwent closed reduction and internal fixation of a femoral neck fracture between 2020 and 2022 were retrospectively included. We measured leg length, femoral offset, and centrum-collum-diaphyseal (CCD) angle in plain radiographs. Scar length, Harris Hip Score, short-form health survey 36-item score (SF-36), and Numeric Rating Scale (NRS) were assessed during follow-up visits. RESULTS: We included 43 patients (22 females) with a median age of 66 (IQR 57, 75). In both groups, leg length differences between the injured and the contralateral side increased, and femoral offset and CCD angle differences were maintained over time. FNS patients had shorter scars and reported fewer emotional problems and more energy. There were no differences between groups regarding the remaining SF-36 sub-scores, Harris Hip Score, and NRS. CONCLUSIONS: The FNS allows for a comparable leg length, femoral offset, and CCD angle reconstruction while achieving similarly high functional and global health scores to the DHS.

Biomarkers for osteoarthritis: Current status and future prospects.

Osteoarthritis (OA) is the most common form of arthritis globally and a major cause of pain, physical disability, and loss of economic productivity, with currently no causal treatment available. This review article focuses on current research on OA biomarkers and the potential for using biomarkers in future clinical practice and clinical trials of investigational drugs. We discuss how biomarkers, specifically soluble ones, have a long path to go before reaching clinical standards of care. We also discuss how biomarkers can help in phenotyping and subtyping to achieve enhanced stratification and move toward better-designed clinical trials. We also describe how biomarkers can be used for molecular endotyping and for determining the clinical outcomes of investigational cell-based therapies. Biomarkers have the potential to be developed as surrogate end points in clinical trials and help private-public consortia and the biotechnology and pharmaceutical industries develop more effective and targeted personalized treatments and enhance clinical care for patients with OA.

Transgenic disruption of endogenous glucocorticoid signaling in osteoblasts does not alter long-term K/BxN serum transfer-induced arthritis.

BACKGROUND: Disruption of glucocorticoid (GC) signaling in osteoblasts results in a marked attenuation of acute antibody-induced arthritis. The role of endogenous GCs in chronic inflammatory arthritis is however not fully understood. Here, we investigated the impact of endogenous GC signaling in osteoblasts on inflammation and bone integrity under chronic inflammatory arthritis by inactivating osteoblastic GC signaling in a long-term K/BxN serum transfer-induced induced arthritis (STIA) model. METHODS: Intracellular GC signaling in osteoblasts was disrupted by transgenic (tg) overexpression of 11beta-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). Inflammatory arthritis was induced in 5-week-old male tg mice and their wild type (WT) littermates by intraperitoneal (i.p.) injection of K/BxN serum while controls (CTRLs) received phosphate-buffered saline (PBS). In a first cohort, K/BxN STIA was allowed to abate until  the endpoint of 42 days (STIA). To mimic rheumatic flares, a second cohort was additionally injected on days 14 and 28 with K/BxN serum (STIA boost). Arthritis severity was assessed daily by clinical scoring and ankle size measurements. Ankle joints were assessed histopathologically. Systemic effects of inflammation on long bone metabolism were analyzed in proximal tibiae by micro-computed tomography (µCT) and histomorphometry. RESULTS: Acute arthritis developed in both tg and WT mice (STIA and STIA boost) and peaked around day 8. While WT STIA and tg STIA mice showed a steady decline of inflammation until day 42, WT STIA boost and tg STIA boost mice exhibited an arthritic phenotype over a period of 42 days. Clinical arthritis severity did not differ significantly between WT and tg mice, neither in the STIA nor in the STIA boost cohorts. Correspondingly, histological indices of inflammation, cartilage damage, and bone erosion showed no significant difference between WT and tg mice on day 42. Histomorphometry revealed an increased bone turnover in tg CTRL and tg STIA boost compared to WT CTRL and WT STIA boost animals, respectively. CONCLUSIONS: In contrast to the previously reported modulating effects of endogenous GC signaling in osteoblasts during acute K/BxN STIA, this effect seems to perish during the chronic inflammatory and resolution phase. These findings indicate that endogenous GC signaling in osteoblasts may mainly be relevant during acute and subacute inflammatory processes.

NOS inhibition reverses TLR2-induced chondrocyte dysfunction and attenuates age-related osteoarthritis.

Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. Although age and joint trauma are prominently associated with OA occurrence, the trigger and signaling pathways propagating their pathogenic aspects are ill defined. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can trigger Toll-like receptors (TLRs). Here we show that TLR2 stimulation suppressed the expression of matrix proteins and induced an inflammatory phenotype in human chondrocytes. Further, TLR2 stimulation impaired chondrocyte mitochondrial function, resulting in severely reduced adenosine triphosphate (ATP) production. RNA-sequencing analysis revealed that TLR2 stimulation upregulated nitric oxide synthase 2 (NOS2) expression and downregulated mitochondria function-associated genes. NOS inhibition partially restored the expression of these genes, and rescued mitochondrial function and ATP production. Correspondingly, Nos2-/- mice were protected from age-related OA development. Taken together, the TLR2-NOS axis promotes human chondrocyte dysfunction and murine OA development, and targeted interventions may provide therapeutic and preventive approaches in OA.

Emergency thoracotomies in traumatic cardiac arrests following blunt trauma - experiences from a German level I trauma center.

PURPOSE: Resuscitative thoracotomies (RT) are the last resort to reduce mortality in patients suffering severe trauma. In recent years, indications for RT have been extended from penetrating to blunt trauma. However, discussions on efficacy are still ongoing, as data on this rarely performed procedure are often scarce. Therefore, this study analyzed RT approaches, intraoperative findings, and clinical outcome measures following RT in patients with cardiac arrest following blunt trauma. METHODS: All patients admitted to our level I trauma center's emergency room (ER) who underwent RT between 2010 and 2021 were retrospectively analyzed. Retrospective chart reviews were performed for clinical data, laboratory values, injuries observed during RT, and surgical procedures. Additionally, autopsy protocols were assessed to describe injury patterns accurately. RESULTS: Fifteen patients were included in this study with a median ISS of 57 (IQR 41-75). The 24-h survival rate was 20%, and the total survival rate was 7%. Three approaches were used to expose the thorax: Anterolateral thoracotomy, clamshell thoracotomy, and sternotomy. A wide variety of injuries were detected, which required complex surgical interventions. These included aortic cross-clamping, myocardial suture repairs, and pulmonary lobe resections. CONCLUSION: Blunt trauma often results in severe injuries in various body regions. Therefore, potential injuries and corresponding surgical interventions must be known when performing RT. However, the chances of survival following RT in traumatic cardiac arrest cases following blunt trauma are small.

Inactivation of the gene encoding procalcitonin prevents antibody-mediated arthritis.

BACKGROUND: Procalcitonin (PCT) is applied as a sensitive biomarker to exclude bacterial infections in patients with rheumatoid arthritis (RA) flare-ups. Beyond its diagnostic value, little is known about the pathophysiological role of PCT in RA. METHODS: Collagen antibody-induced arthritis (CAIA) was induced in Calca-deficient mice (Calca-/-), lacking PCT (n = 15), and wild-type (WT) mice (n = 13), while control (CTRL) animals (n = 8 for each genotype) received phosphate-buffered saline. Arthritis severity and grip strength were assessed daily for 10 or 48 days. Articular inflammation, cartilage degradation, and bone lesions were assessed by histology, gene expression analysis, and µ-computed tomography. RESULTS: Serum PCT levels and intra-articular PCT expression increased following CAIA induction. While WT animals developed a full arthritic phenotype, Calca-deficient mice were protected from clinical and histological signs of arthritis and grip strength was preserved. Cartilage turnover markers and Tnfa were exclusively elevated in WT mice. Calca-deficient animals expressed increased levels of Il1b. Decreased bone surface and increased subchondral bone porosity were observed in WT mice, while Calca-deficiency preserved bone integrity. CONCLUSION: The inactivation of Calca and thereby PCT provided full protection from joint inflammation and arthritic bone loss in mice exposed to CAIA. Together with our previous findings on the pathophysiological function of Calca-derived peptides, these data indicate an independent pro-inflammatory role of PCT in RA.

Individual immune cell and cytokine profiles determine platelet-rich plasma composition.

OBJECTIVE: Platelet-rich plasma (PRP) therapy is increasingly popular to treat musculoskeletal diseases, including tendinopathies and osteoarthritis (OA). To date, it remains unclear to which extent PRP compositions are determined by the immune cell and cytokine profile of individuals or by the preparation method. To investigate this, we compared leukocyte and cytokine distributions of different PRP products to donor blood samples and assessed the effect of pro-inflammatory cytokines on chondrocytes. DESIGN: For each of three PRP preparations (ACP®, Angel™, and nSTRIDE® APS), products were derived using whole blood samples from twelve healthy donors. The cellular composition of PRP products was analyzed by flow cytometry using DURAClone antibody panels (DURAClone IM Phenotyping Basic and DURAClone IM T Cell Subsets). The MESO QuickPlex SQ 120 system was used to assess cytokine profiles (V-PLEX Proinflammatory Panel 1 Human Kit, Meso Scale Discovery). Primary human chondrocyte 2D and 3D in vitro cultures were exposed to recombinant IFN-γ and TNF-α. Proliferation and chondrogenic differentiation were quantitatively assessed. RESULTS: All three PRP products showed elevated portions of leukocytes compared to baseline levels in donor blood. Furthermore, the pro-inflammatory cytokines IFN-γ and TNF-α were significantly increased in nSTRIDE® APS samples compared to donor blood and other PRP products. The characteristics of all other cytokines and immune cells from the donor blood, including pro-inflammatory T cell subsets, were maintained in all PRP products. Chondrocyte proliferation was impaired by IFN-γ and enhanced by TNF-α treatment. Differentiation and cartilage formation were compromised upon treatment with both cytokines, resulting in altered messenger ribonucleic acid (mRNA) expression of collagen type 1A1 (COL1A1), COL2A1, and aggrecan (ACAN) as well as reduced proteoglycan content. CONCLUSIONS: Individuals with elevated levels of cells with pro-inflammatory properties maintain these in the final PRP products. The concentration of pro-inflammatory cytokines strongly varies between PRP products. These observations may help to unravel the previously described heterogeneous response to PRP in OA therapy, especially as IFN-γ and TNF-α impacted primary chondrocyte proliferation and their characteristic gene expression profile. Both the individual's immune profile and the concentration method appear to impact the final PRP product. TRIAL REGISTRATION: This study was prospectively registered in the Deutsches Register Klinischer Studien (DRKS) on 4 November 2021 (registration number DRKS00026175).

Optimization of chondrocyte isolation from human articular cartilage to preserve the chondrocyte transcriptome.

The isolation of chondrocytes from human articular cartilage for single-cell RNA sequencing requires extensive and prolonged tissue digestion at 37 C. Modulations of the transcriptional activity likely take place during this period such that the transcriptomes of isolated human chondrocytes no longer match their original status in vivo. Here, we optimized the human chondrocyte isolation procedure to maximally preserve the in vivo transcriptome. Cartilage tissues were transferred into a hypoxia chamber (4% O2) immediately after being removed from OA patients and minced finely. Collagenase II at concentrations of 0.02%, 0.1%, 0.25%, 0.5%, 1%, and 2% was applied for 0.5, 1, 2, 4, and 18 h to digest the minced tissue. Actinomycin D (ActD) was added to test its capacity in stabilizing the transcriptome. Cell yield, viability, cell size, and transcriptome were determined using counter chamber, flow cytometry, and RNA sequencing (RNA-seq). Collagenase II at 2% concentration released small chondrocytes from cartilage matrix during the first digestion hour and started to release large cells thereafter, reaching a complete release at 4 h. During 4-h digestions, collagenase II at 2% and 1% but not at lower concentrations yielded maximal release also of the large chondrocyte population. RNA-seq analysis revealed that a 4-h digestion period with 1% or 2% collagenase II plus Actinomycin D optimally preserved the transcriptome. Thus, this study provides an isolation protocol for single chondrocytes from human articular cartilage optimized for transcriptome preservation and RNA-seq analysis.

Standardized protocol and outcome measurements for the collagen antibody-induced arthritis mouse model.

The murine collagen antibody-induced arthritis (CAIA) model resembles various features of human rheumatoid arthritis and is based on the intraperitoneal or intravenous injection of autoantibodies against type II collagen. Here, we present a standardized protocol for the intraperitoneal injection of arthritis-inducing autoantibodies in mice, followed by a description of daily arthritis assessments. We then detail the steps to harvest joint and bone tissues for histological, radiological, and molecular analyses. We highlight animal welfare and 3R considerations for experimental arthritis studies. For complete details on the use and execution of this protocol, please refer to Maleitzke et al. (2021, 2022).

Quality and quantity of serious violent suicide attempts during the COVID-19 pandemic.

Background: While repeated shutdown and lockdown measures helped contain the spread of SARS-CoV-2 during the COVID-19 pandemic, social distancing and self-isolation negatively impacted global mental health in 2020 and 2021. Although suicide rates did reportedly not increase during the first months of the pandemic, long-term data, and data on the quality of serious violent suicide attempts (SVSAs) are not available to date. Materials and methods: Orthopaedic trauma patient visits to the emergency department (ED), ED trauma team activations, and SVSAs were retrospectively evaluated from January 2019 until May 2021 in four Level-I Trauma Centers in Berlin, Germany. SVSAs were assessed for suicide method, injury pattern and severity, type of treatment, and length of hospital stay. Results: Significantly fewer orthopaedic trauma patients presented to EDs during the pandemic (n = 70,271) compared to the control (n = 84,864) period (p = 0.0017). ED trauma team activation numbers remained unchanged. SVSAs (corrected for seasonality) also remained unchanged during control (n = 138) and pandemic (n = 129) periods, and no differences were observed for suicide methods, injury patterns, or length of hospital stay. Conclusion: Our data emphasize that a previously reported rise in psychological stress during the COVID-19 pandemic does not coincide with increased SVSA rates or changes in quality of SVSAs.

Source and hub of inflammation: The infrapatellar fat pad and its interactions with articular tissues during knee osteoarthritis.

Knee osteoarthritis, the most prevalent degenerative joint disorder worldwide, is driven by chronic low-grade inflammation and subsequent cartilage degradation. Clinical data on the role of the Hoffa or infrapatellar fat pad in knee osteoarthritis are, however, scarce. The infrapatellar fat pad is a richly innervated intracapsular, extrasynovial adipose tissue, and an abundant source of adipokines and proinflammatory and catabolic cytokines, which may contribute to chronic synovial inflammation, cartilage destruction, and subchondral bone remodeling during knee osteoarthritis. How the infrapatellar fat pad interacts with neighboring tissues is poorly understood. Here, we review available literature with regard to the infrapatellar fat pad's interactions with cartilage, synovium, bone, menisci, ligaments, and nervous tissue during the development and progression of knee osteoarthritis. Signaling cascades are described with a focus on immune cell populations, pro- and anti-inflammatory cytokines, adipokines, mesenchymal stromal cells, and molecules derived from conditioned media from the infrapatellar fat pad. Understanding the complex interplay between the infrapatellar fat pad and its neighboring articular tissues may help to better understand and treat the multifactorial pathogenesis of osteoarthritis.

Changes of radiological examination volumes over the course of the COVID-19 pandemic: a comprehensive analysis of the different waves of infection.

OBJECTIVES: Data from radiological departments provide important information on overall quantities of medical care provided. With this study we used a comprehensive analysis of radiological examinations as a surrogate marker to quantify the effect of the different COVID-19 waves on medical care provided. METHODS: Radiological examination volumes during the different waves of infection were compared among each other as well as to time-matched control periods from pre-pandemic years using a locally weighted scatterplot smoothing as well as negative binominal regression models. RESULTS: A total of 1,321,119 radiological examinations were analyzed. Examination volumes were reduced by about 10% over the whole study period (IRR = 0.90; 95% CI 0.89-0.92), with a focus on acute medical care (0.84; 0.83-0.85) and outpatients (0.93: 0.90-0.97). When compared to wave 1, examination volumes were about 17% higher during wave 2 (1.17; 1.10-1.25), and 33% higher in wave 3 of the pandemic (1.33; 1.24-1.42). CONCLUSIONS: This study shows the severe effect of COVID-19 pandemic and related shutdown measures on overall provided medical care as measured by radiological examinations. When compared, the decrease of medical care was more pronounced in the earlier waves of the pandemic.

Metabolic reprogramming of synovial fibroblasts in osteoarthritis by inhibition of pathologically overexpressed pyruvate dehydrogenase kinases.

Osteoarthritis (OA) is the most common degenerative joint disease and a major cause of age-related disability worldwide, mainly due to pain, the disease's main symptom. Although OA was initially classified as a non-inflammatory joint disease, recent attention has been drawn to the importance of synovitis and fibroblast-like synoviocytes (FLS) in the pathogenesis of OA. FLS can be divided into two major populations: thymus cell antigen 1 (THY1)- FLS are currently classified as quiescent cells and assumed to destroy bone and cartilage, whereas THY1+ FLS are invasively proliferative cells that drive synovitis. Both THY1- and THY1+ FLS share many characteristics with fibroblast-like progenitors - mesenchymal stromal cells (MSC). However, it remains unclear whether synovitis-induced metabolic changes exist in FLS from OA patients and whether metabolic differences may provide a mechanistic basis for the identification of approaches to precisely convert the pathologically proliferative synovitis-driven FLS phenotype into a healthy one. To identify novel pathological mechanisms of the perpetuation and manifestation of OA, we analyzed metabolic, proteomic, and functional characteristics of THY1+ FLS from patients with OA. Proteome data and pathway analysis revealed that an elevated expression of pyruvate dehydrogenase kinase (PDK) 3 was characteristic of proliferative THY1+ FLS from patients with OA. These FLS also had the highest podoplanin (PDPN) expression and localized to the sublining but also the lining layer in OA synovium in contrast to the synovium of ligament trauma patients. Inhibition of PDKs reprogrammed metabolism from glycolysis towards oxidative phosphorylation and reduced FLS proliferation and inflammatory cytokine secretion. This study provides new mechanistic insights into the importance of FLS metabolism in the pathogenesis of OA. Given the selective overexpression of PDK3 in OA synovium and its restricted distribution in synovial tissue from ligament trauma patients and MSC, PDKs may represent attractive selective metabolic targets for OA treatment. Moreover, targeting PDKs does not affect cells in a homeostatic, oxidative state. Our data provide an evidence-based rationale for the idea that inhibition of PDKs could restore the healthy THY1+ FLS phenotype. This approach may mitigate the progression of OA and thereby fundamentally change the clinical management of OA from the treatment of symptoms to addressing causes.

Intramuscular and intratendinous placenta-derived mesenchymal stromal-like cell treatment of a chronic quadriceps tendon rupture.

BACKGROUND: Quadriceps tendon ruptures (QTRs) are rare but debilitating injuries, often associated with chronic metabolic conditions or long-term steroid treatment. While the surgical treatment for acute QTRs is described thoroughly, no common strategy exists for the often frustrating treatment of chronic, reoccurring QTRs. The pro-angiogenic and immunomodulatory properties of placenta-derived adherent mesenchymal stromal-like (PLX-PAD) cells have been described to protect musculoskeletal tissues from inflammation and catabolic cytokine migration, yet little is known about the regenerative potential of PLX-PAD cells in repetitively damaged tendon tissue. CASE: We report the case of an 80-year-old male patient with a chronic three-time QTR of his right knee. The quadriceps tendon was reconstructed applying a conventional suture anchor repair procedure combined with a synthetic mesh augmentation and additional intramuscular and intratendineous PLX-PAD cell injections as an individualized treatment approach. No adverse events were reported, and excellent radiological and functional outcomes with a passive range of motion of 0/0/120° knee extension-flexion were observed at the 12 month follow-up. Gait analysis confirmed restoration of joint motion, including gait speed, deficit in step length, and knee extensor muscle strength (pre-surgery: 0.98 m/s, 40 cm, 42.4 ± 12.4 N; 9 months post-surgery: 1.07 m/s, 0 cm, 10.4 ± 18.9 N) as well as hyperextension throughout stance and late swing phases (pre-surgery: -11.2 ± 0.9°; 9 months post-surgery: -2.7 ± 1.6°). Postoperative lymphocyte and cytokine analyses from the patient's peripheral blood serum suggested a systemic short-term immunoregulatory reaction with postoperatively increased interleukin (IL)-6 (pre-surgery: 0.79 pg/mL; day 1: 139.97 pg/mL; day 5: 5.58 pg/mL; 9 months: 1.76 pg/mL) and IL-10 (pre-surgery: 0.9 pg/mL; day 1: 1.21 pg/ mL; day 5: 0.3 pg/mL; 9 months: 0.34 pg/mL) levels that decreased again over time. CONCLUSIONS: Herein, we demonstrate a successfully treated chronic QTR with a synergistic surgical and biological reconstructive treatment approach. This local add-on treatment with PLX-PAD cells may be considered in specific cases of chronic QTRs, not susceptible to traditional suture anchor procedures and which exhibit a high risk of treatment failure. Further scientific engagement is warranted to explore underlying immunomodulatory mechanisms of action behind PLX-PAD cell treatment for tendon injuries.

The calcitonin receptor protects against bone loss and excessive inflammation in collagen antibody-induced arthritis.

Pharmacological application of teleost calcitonin (CT) has been shown to exert chondroprotective and anti-resorptive effects in patients with rheumatoid arthritis (RA). However, the role of endogenous CT that signals through the calcitonin receptor (CTR) remains elusive. Collagen II antibody-induced arthritis (CAIA) was stimulated in wild type (WT) and CTR-deficient (Calcr-/-) mice. Animals were monitored over 10 or 48 days. Joint inflammation, cartilage degradation, and bone erosions were assessed by clinical arthritis score, histology, histomorphometry, gene expression analysis, and µ-computed tomography. CAIA was accompanied by elevated systemic CT levels and CTR expression in the articular cartilage. Inflammation, cartilage degradation, and systemic bone loss were more pronounced in Calcr-/- CAIA mice. Expression of various pro-inflammatory, bone resorption, and catabolic cartilage markers were exclusively increased in Calcr-/- CAIA mice. Endogenous CT signaling through the mammalian CTR has the potential to protect against joint inflammation, cartilage degradation, and excessive bone remodeling in experimental RA.

Routine laboratory parameters predict intensive care unit admission and hospitalization in patients suffering stab injuries.

Background: Knife crime has increased considerably in recent years in Northern Europe. Affected patients often require immediate surgical care due to traumatic organ injury. Yet, little is known about clinically relevant routine laboratory parameters in stab injury patients and how these are associated with intensive care unit (ICU) admission, hospitalization and number of surgeries. Methods: We retrospectively analyzed 258 stab injury cases between July 2015 and December 2021 at an urban Level I Trauma Center. Annual and seasonal incidences, injury site, injury mechanism, Injury Severity Score (ISS), and surgical management were evaluated. First, correlations between routine laboratory parameters for hematology, coagulation, and serum biochemistry (peak, and Δ (change from admission to peak within 3 days following admission)) and length of hospital stay, ICU stay, and number of surgeries were assessed using Spearman's rank correlation coefficients. Second, multivariable Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were conducted to identify parameters predictive of clinical outcomes. Third, longitudinal developments of routine laboratory parameters were assessed during hospital admission. Results: In 2021, significantly more stab injuries were recorded compared with previous years and occurred less during winter compared with other seasons. Mean ISS was 8.3 ± 7.3, and ISS was positively correlated with length of hospital and ICU stay (r = 0.5-0.8, p < 0.001). Aspartate transaminase (AST) (Δ) (r = 0.690), peak C-reactive protein (CrP) (r = 0.573), and erythrocyte count (Δ) (r = 0.526) showed the strongest positive correlations for length of ICU stay for penetrating, thoracoabdominal, and organ injuries, respectively. No correlations were observed between routine laboratory parameters and number of surgeries. For patients with penetrating injuries, LASSO-selected predictors of ICU admission included ISS, pH and lactate at admission, and Δ values for activated partial thromboplastin time (aPTT), K+, and erythrocyte count. CrP levels on day 3 were significantly higher in patients with penetrating (p = 0.005), thoracoabdominal (p = 0.041), and organ injuries (p < 0.001) compared with those without. Conclusion: Our data demonstrate an increase in stab injury cases in 2021 and an important link between changes in routine laboratory parameters and ICU admission and hospitalization. Monitoring ISS and changes in AST, CrP, erythrocyte count, pH, lactate, aPTT, and K+ may be useful to identify patients at risk and adjust surgical and ICU algorithms early on.