Baricitinib ameliorates inflammatory and neuropathic pain in collagen antibody-induced arthritis mice by modulating the IL-6/JAK/STAT3 pathway and CSF-1 expression in dorsal root ganglion neurons.

BACKGROUND: Janus kinase (JAK) inhibitors, such as baricitinib, are widely used to treat rheumatoid arthritis (RA). Clinical studies show that baricitinib is more effective at reducing pain than other similar drugs. Here, we aimed to elucidate the molecular mechanisms underlying the pain relief conferred by baricitinib, using a mouse model of arthritis. METHODS: We treated collagen antibody-induced arthritis (CAIA) model mice with baricitinib, celecoxib, or vehicle, and evaluated the severity of arthritis, histological findings of the spinal cord, and pain-related behaviours. We also conducted RNA sequencing (RNA-seq) to identify alterations in gene expression in the dorsal root ganglion (DRG) following baricitinib treatment. Finally, we conducted in vitro experiments to investigate the direct effects of baricitinib on neuronal cells. RESULTS: Both baricitinib and celecoxib significantly decreased CAIA and improved arthritis-dependent grip-strength deficit, while only baricitinib notably suppressed residual tactile allodynia as determined by the von Frey test. CAIA induction of inflammatory cytokines in ankle synovium, including interleukin (IL)-1ß and IL-6, was suppressed by treatment with either baricitinib or celecoxib. In contrast, RNA-seq analysis of the DRG revealed that baricitinib, but not celecoxib, restored gene expression alterations induced by CAIA to the control condition. Among many pathways changed by CAIA and baricitinib treatment, the interferon-alpha/gamma, JAK-signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) pathways were considerably decreased in the baricitinib group compared with the celecoxib group. Notably, only baricitinib decreased the expression of colony-stimulating factor 1 (CSF-1), a potent cytokine that causes neuropathic pain through activation of the microglia-astrocyte axis in the spinal cord. Accordingly, baricitinib prevented increases in microglia and astrocytes caused by CAIA. Baricitinib also suppressed JAK/STAT3 pathway activity and Csf1 expression in cultured neuronal cells. CONCLUSIONS: Our findings demonstrate the effects baricitinib has on the DRG in relation to ameliorating both inflammatory and neuropathic pain.

Runx2 and Runx3 differentially regulate articular chondrocytes during surgically induced osteoarthritis development.

The Runt-related transcription factor (Runx) family plays various roles in the homeostasis of cartilage. Here, we examined the role of Runx2 and Runx3 for osteoarthritis development in vivo and in vitro. Runx3-knockout mice exhibited accelerated osteoarthritis following surgical induction, accompanied by decreased expression of lubricin and aggrecan. Meanwhile, Runx2 conditional knockout mice showed biphasic phenotypes: heterozygous knockout inhibited osteoarthritis and decreased matrix metallopeptidase 13 (Mmp13) expression, while homozygous knockout of Runx2 accelerated osteoarthritis and reduced type II collagen (Col2a1) expression. Comprehensive transcriptional analyses revealed lubricin and aggrecan as transcriptional target genes of Runx3, and indicated that Runx2 sustained Col2a1 expression through an intron 6 enhancer when Sox9 was decreased. Intra-articular administration of Runx3 adenovirus ameliorated development of surgically induced osteoarthritis. Runx3 protects adult articular cartilage through extracellular matrix protein production under normal conditions, while Runx2 exerts both catabolic and anabolic effects under the inflammatory condition.

Relationship between the Accuracy of the Acetabular Cup Angle and BMI in Posterolateral Total Hip Arthroplasty with CT-Based Navigation.

Background and Objectives: Precise acetabular cup placement is essential for successful total hip arthroplasty (THA). In obese patients, its accuracy is often difficult to achieve because of the thickness of the soft tissues. This study aimed to determine the relationship between the accuracy of acetabular cup angle and body mass index (BMI) in posterolateral THA using the computed tomography-based navigation (CT-navi) system. Materials and Methods: We retrospectively reviewed 145 consecutive primary THAs using the CT-navi system between January 2015 and January 2018. All surgeries were performed using cementless cups employing the posterolateral approach with the patient in the decubitus position. We compared the radiographic inclination and anteversion obtained intraoperatively from the CT-navi with those measured by postoperative CT using three-dimensional templating software. We evaluated the relationship between the extent of errors and correlation with BMI. Results: In non-overweight patients (BMI < 25, 88 hips), the mean navigation errors for inclination were 2.8 ± 2.2° and for anteversion were 2.6 ± 2.3°. Meanwhile, in overweight patients (BMI ≥ 25, 57 hips), the mean navigation errors were 2.6 ± 2.4° for inclination and 2.4 ± 2.4° for anteversion. We found no significant difference between overweight and non-overweight patients in both inclination and anteversion. There was no correlation between the extent of errors and BMI. Conclusions: In posterolateral THA, CT-navi can aid the precise placement of the acetabular cup irrespective of a patient's BMI.

Comparison between cup implantations during total hip arthroplasty with or without a history of rotational acetabular osteotomy.

INTRODUCTION: Total hip arthroplasty (THA) after rotational acetabular osteotomy (RAO) is technically demanding because of the characteristic acetabular morphology after RAO. The present study aimed to investigate the differences in the three-dimensional cup position between THA after RAO and primary THA. MATERIALS AND METHODS: We analysed the pre-operative and post-operative computed tomography (CT) data of 120 patients (20 patients after RAO and 100 patients without a history of RAO) who underwent THA between January 2017 and June 2018. We evaluated radiographic parameters, including acetabular anteversion, antero-posterior distance at the level of the femoral head centre, the presence of anterior acetabular osteophyte and/or rotated fragment during RAO from the CT data. Additionally, operative data and clinical scores were also evaluated. RESULTS: Although we found no significant differences in any clinical parameters, there were significant differences in radiographic parameters and operative data. The morphology of the acetabulum was significantly retroverted, and the antero-posterior distance was longer in patients after RAO, compared to the implanted cup. Additionally, longer operative time was necessary for such patients. These results reflect the atypical acetabular morphology after RAO, and emphasize that care should be taken to avoid anterior bony impingement and post-operative dislocation. CONCLUSION: For cup implantation during THA after RAO, surgeons should acknowledge the atypical morphology of the acetabulum and not be misled by its visual shape.

Divergence in chondrogenic potential between in vitro and in vivo of adipose- and synovial-stem cells from mouse and human.

BACKGROUND: Somatic stem cell transplantation has been performed for cartilage injury, but the reparative mechanisms are still conflicting. The chondrogenic potential of stem cells are thought as promising features for cartilage therapy; however, the correlation between their potential for chondrogenesis in vitro and in vivo remains undefined. The purpose of this study was to investigate the intrinsic chondrogenic condition depends on cell types and explore an indicator to select useful stem cells for cartilage regeneration. METHODS: The chondrogenic potential of two different stem cell types derived from adipose tissue (ASCs) and synovium (SSCs) of mice and humans was assessed using bone morphogenic protein-2 (BMP2) and transforming growth factor-ß1 (TGFß1). Their in vivo chondrogenic potential was validated through transplantation into a mouse osteochondral defect model. RESULTS: All cell types showed apparent chondrogenesis under the combination of BMP2 and TGFß1 in vitro, as assessed by the formation of proteoglycan- and type 2 collagen (COL2)-rich tissues. However, our results vastly differed with those observed following single stimulation among species and cell types; apparent chondrogenesis of mouse SSCs was observed with supplementation of BMP2 or TGFß1, whereas chondrogenesis of mouse ASCs and human SSCs was observed with supplementation of BMP2 not TGFß1. Human ASCs showed no obvious chondrogenesis following single stimulation. Mouse SSCs showed the formation of hyaline-like cartilage which had less fibrous components (COL1/3) with supplementation of TGFß1. However, human cells developed COL1/3+ tissues with all treatments. Transcriptomic analysis for TGFß receptors and ligands of cells prior to chondrogenic induction did not indicate their distinct reactivity to the TGFß1 or BMP2. In the transplanted site in vivo, mouse SSCs formed hyaline-like cartilage (proteoglycan+/COL2+/COL1-/COL3-) but other cell types mainly formed COL1/3-positive fibrous tissues in line with in vitro reactivity to TGFß1. CONCLUSION: Optimal chondrogenic factors driving chondrogenesis from somatic stem cells are intrinsically distinct among cell types and species. Among them, the response to TGFß1 may possibly represent the fate of stem cells when locally transplanted into cartilage defects.

Fracture of ossified Achilles tendons: A review of cases.

Fracture of an ossification of the Achilles tendon (OAT) is a rare entity, and its etiology, pathology, and treatment remain unclear. We reviewed and scrutinized 18 cases (16 articles) of the fracture of an OAT. The most common etiologies of the ossifications include previous surgery and trauma. The fractures often occur without any trigger or with minimal trigger. The long, > 5 cm, ossification in the body of the Achilles tendon may have a higher risk of fracture. The OAT itself is often asymptomatic; however, its fracture causes severe local pain, swelling, and weakness of plantar flexion, which forces patients to undergo aggressive treatments. Regarding the treatments of the fractures, nonoperative treatment by immobilizing ankle joint could be an option for elderly patients. However, because it often cannot produce satisfactory results in younger patients, surgical treatment is typically recommended. Excision of the fractured mass and repairing the tendon is applicable if the remnant is enough. If there is a defect after the excision, reconstruction with autologous grafts or adjacent tendon transfer is performed. Gastrocnemius fascia turndown flap, hamstring tendon and tensor fascia lata are used as autologous grafts, whereas peroneus brevis and flexor hallucis longus tendons are used for the tendon transfer. If the fracture of an OAT is treated properly, the functional result will be satisfactory.

Severe osteolysis and periprosthetic femoral fracture 45 years after acrylic hemiarthroplasty of the hip: a case report.

BACKGROUND: Hip arthroplasty using acrylic prosthesis was once conducted; however, it has now been abandoned because of early breakages and wear of material. Therefore, complications or revision surgeries due to the use of acrylic prostheses are becoming rare. CASE PRESENTATION: A 76-year-old woman presented with a sudden onset of severe pain in her left femur while walking. Radiographs revealed severe osteolysis and periprosthetic femoral fracture 45 years after the initial hemiarthroplasty using an acrylic prosthesis. We performed a Girdlestone resection arthroplasty by removing the prosthesis and fixing the fracture site using an intramedullary nail and metal plate. The patient was pain-free in her hip and leg 2 years and 9 months after the surgery. Although she walked with a cane or crutches, no postoperative complications were observed. CONCLUSIONS: The combined use of an intramedullary nail and plate fixation with resection arthroplasty could offer acceptable results for patients with severe osteolysis and periprosthetic fracture after femoral head replacement using an acrylic prosthesis. Our report seems relevant because it not only reminds us of the significant steps made in the development of modern total hip arthroplasty; it also highlights one of the surgical options for severe osteolysis and periprosthetic fracture of the hip.

Characteristics of three-dimensional acetabular morphology of patients with excellent outcome after rotational acetabular osteotomy over 20 years.

BACKGROUND: Rotational acetabular osteotomy (RAO) is a type of pelvic osteotomy performed to improve the acetabular bony coverage against the femoral head for patients with acetabular dysplasia. The acetabular bony coverage is ideally evaluated three-dimensionally; however, there is a paucity of published data regarding three-dimensional morphology in patients with long-term excellent outcome after RAO. The present study investigated the characteristics of three-dimensional acetabular morphology with long-term excellent outcome after RAO in comparison to patients with normal hip joints and those converted to total hip arthroplasty (THA) after RAO because of osteoarthritis (OA) progression. METHODS: Anteroposterior plain radiograph and computed tomography data of 57 hip joints (17 joints with excellent outcome 20 years or more after RAO, 16 normal joints, and 20 joints converted to THA after RAO) were analyzed. The two-dimensional lateral center-edge (CE) angle from plain radiographs and acetabular anteversion, anterior acetabular sector angle, and posterior sector angle from computed tomography (CT) images were calculated. RESULTS: Compared with patients converted to THA, all parameters in patients with long-term excellent outcome after RAO were similar to those in patients with normal hip joints, particularly in the three-dimensional analyses. The anterior bony coverage was excessive, whereas the posterior bony coverage was deficient in patients converted to THA after RAO. Anterior bony impingement and posterior instability may be the cause of OA progression after RAO. CONCLUSION: Caution must be taken to avoid rotating the separated fragment excessively to the anterior direction during RAO to prevent OA progression and achieve long-term excellent outcome.

The Utility of the Energy Subtraction Method for Thoracic Spine Radiography in Clinical Practice: An Analysis of 25 Patients With Multiple Myeloma.

Interpretation of thoracic spine radiographs is difficult because they cannot clearly depict the vertebrae due to overlap with soft tissues. This study aimed to evaluate whether thoracic spine radiographs obtained using the energy subtraction method could improve the accuracy of a diagnosis of thoracic osteolytic lesions. The authors analyzed 300 thoracic vertebrae from 25 patients with multiple myeloma who underwent thoracic spine radiography. All patients underwent thoracic spine radiography with 2 views. Two sets of images were prepared: computed radiography images (CR images) acquired using conventional processing parameters; and processed images for specifically visualizing bone, using the energy subtraction method (ES images). The CR images (CR group) and paired CR and ES images (CR+ES group) were interpreted in parallel by 5 orthopedic surgeons. The presence of osteolytic lesions was evaluated for each of the 12 thoracic vertebrae, and the sensitivity and specificity of the method were compared with computed tomography (CT), which is considered the gold standard. Subgroup analysis was also performed based on location. Osteolytic lesions were found on CT in 28 (9.3%) vertebrae of 12 patients. The overall sensitivities and specificities of the CR and CR+ES groups were 17.2% and 54.3%, respectively, and 95.6% and 98.0%, respectively, with statistically significant differences. Subgroup analysis showed particular improvement in the sensitivity for the CR+ES group in the middle thoracic spine compared with that at other locations. Thoracic spine radiographs generated using this method may improve the accuracy of diagnosis of thoracic osteolytic lesions. [Orthopedics. 2021;44(1):e31-e35.].

Midterm results of revision total hip arthroplasty for migrated bipolar hemiarthroplasty in patients with hip osteoarthritis using cementless cup with the rim-fit technique.

PURPOSE: The results of reamed bipolar hemiarthroplasty (BHA) in patients with hip osteoarthritis (OA) are reported to be unfavorable. Acetabular reaming for sufficient bony coverage caused bipolar head migration into the superomedial direction, and most patients required revision surgeries. Several methods are applicable to treat decreased bone stock. This study aimed to investigate the midterm results of revision surgeries using the cementless cup with the rim-fit technique. METHODS: Between 1996 and 2014, acetabular revision surgeries using the cementless cup with the rim-fit technique were performed in 86 hips (74 patients). We evaluated radiographic outcomes, including positional change of the rotation center of the artificial femoral head, presence of implant loosening, and filling of the initial gap. We also evaluated clinical outcomes, including the Harris hip score (HHS), and postoperative complications. RESULTS: The average positional changes from BHA to prerevision surgeries were 8.0 mm superiorly and 4.1 mm medially. The average changes from prerevision to postrevision surgeries were 3.7 mm inferiorly and 2.4 mm laterally. No implant loosening was found in all cases; the initial gap between the acetabular host bone and the acetabular cup was filled in 53 (93%) among 57 hips. The average HHS improved from 65.9 before revision surgeries to 83.8 in the latest follow-up. Dislocation and postoperative periprosthetic fracture occurred in two and five hips, respectively; no cases required rerevision surgeries. CONCLUSION: There were favorable midterm results of the revision total hip arthroplasty for migrated BHA in patients with hip OA using cementless cup with the rim-fit technique.

Risk factors for incidental durotomy during posterior open spine surgery for degenerative diseases in adults: A multicenter observational study.

Incidental durotomy (ID) is a common intraoperative complication of spine surgery. It can lead to persistent cerebrospinal fluid leakage, which may cause serious complications, including severe headache, pseudomeningocele formation, nerve root entrapment, and intracranial hemorrhage. As a result, it contributes to higher healthcare costs and poor patient outcomes. The purpose of this study was to clarify the independent risk factors that can cause ID during posterior open spine surgery for degenerative diseases in adults. We conducted a prospective multicenter study of adult patients who underwent posterior open spine surgery for degenerative diseases at 10 participating hospitals from July 2010 to June 2013. A total of 4,652 consecutive patients were enrolled. We evaluated potential risk factors, including age, sex, body mass index, American Society of Anesthesiologists physical status classification, the presence of diabetes mellitus, the use of hemodialysis, smoking status, steroid intake, location of the surgery, type of operative procedure, and past surgical history in the operated area. A multivariate logistic regression analysis was performed to identify the risk factors associated with ID. The incidence of ID was 8.2% (380/4,652). Corrective vertebral osteotomy and revision surgery were identified as independent risk factors for ID, while cervical surgery and discectomy were identified as factors that independently protected against ID during posterior open spine surgery for degenerative diseases in adults. Therefore, we identified 2 independent risk factors for and 2 protective factors against ID. These results may contribute to making surgeons aware of the risk factors for ID and can be used to counsel patients on the risks and complications associated with open spine surgery.

Clinical and Radiographic Outcomes of Total Hip Arthroplasty With a Specific Liner in Small Asian Patients: Influence of Patient-Related, Implant-Related, and Surgical Factors on Femoral Head Penetration.

BACKGROUND: We evaluated the clinical and radiographic outcomes, including femoral head penetration, of total hip arthroplasty performed using a specific polyethylene (PE) liner in small Asian patients at 10 years after the index surgery. In addition, we investigated whether femoral head penetration was affected by patient-related, implant-related, and surgical factors. METHODS: Between August 2002 and June 2005, for cementless primary total hip arthroplasty, we used acetabular PE liners that were manufactured from GUR 1050 resin, machined from isostatic compression-molded bar stock, and sterilized with a gamma ray irradiation in argon gas. We assessed 82 hips in 78 patients who received these liners. RESULTS: The mean Harris hip score improved from 41.0 preoperatively to 84.5 at 10 years postoperatively. Periprosthetic osteolysis was observed in 7 hips (9.8%). No acetabular component migration was detected, and no revision surgery was performed 10 years postoperatively. The mean steady-state wear rate was 0.031 mm/y, which was lower than the wear rate for other conventional PE liners of the previous studies. Among the patient-related, implant-related, and surgical factors, sex was significantly associated with the mean steady-state wear rate, with a higher rate in male patients than in female patients. CONCLUSION: PE acetabular liners used in small Asian patients show similar clinical outcomes and reduced wear compared with those of other liners. In addition, sex is significantly associated with the mean steady-state wear rate, and the steady-state wear rate is higher in male patients than in female patients.

Successful treatment of a fracture of a huge Achilles tendon ossification with autologous hamstring tendon graft and gastrocnemius fascia flap: a case report.

BACKGROUND: Fracture of an ossified Achilles tendon is a rare entity, and no standard treatment has been established. This is the first report to describe the use of a hamstring tendon graft and gastrocnemius fascia flap for Achilles tendon reconstruction. CASE PRESENTATION: We present the case of a 50-year-old woman with fracture of an ossified Achilles tendon. She presented to our clinic with acute right hindfoot pain, which started suddenly while going up the stairs. Plain radiography and magnetic resonance imaging revealed a massive ossification on the right Achilles tendon extending over 14 cm in length; the ossification was fractured at 5 cm proximal to the calcaneus insertion. Surgical treatment included removal of the ossified tendon and reconstruction with an autologous hamstring tendon graft and gastrocnemius fascia flap. One year after surgery, she was able to walk with little pain or discomfort and to stand on her right tiptoe. CONCLUSION: Our novel surgical procedure may be useful in the treatment of fractured ossified Achilles tendons and large Achilles tendon defects.