Histopathological Confirmation of Axonal Sprouting in Regenerative Peripheral Nerve Interface.

Symptomatic neuroma represents a debilitating complication after major limb amputation. The regenerative peripheral nerve interface (RPNI) has emerged as a reproducible and practical surgery aimed at mitigating the formation of painful neuroma. Although previous animal studies revealed axonal sprouting, elongation, and synaptogenesis of proximal nerve stump within the muscle graft in RPNI, there is a lack of reports confirming these physiological reactions at the histopathological level in human samples. This report presents a case of below-knee amputation with RPNI due to foot gangrene resulting from polyarteritis nodosa. Subsequently, an above-knee amputation was necessitated due to the exacerbation of polyarteritis nodosa, providing the opportunity for histopathological examination of the RPNI site. The examination revealed sprouting, elongation, and existence of neuromuscular junction of the tibial nerve within the grafted muscle. To the best of our knowledge, this is the first report demonstrating axonal sprouting, elongation, and possibility of synaptogenesis of the nerve stump within the grafted muscle in a human sample.

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.

RSPO2 defines a distinct undifferentiated progenitor in the tendon/ligament and suppresses ectopic ossification.

Ectopic endochondral ossification in the tendon/ligament is caused by repetitive mechanical overload or inflammation. Tendon stem/progenitor cells (TSPCs) contribute to tissue repair, and some express lubricin [proteoglycan 4 (PRG4)]. However, the mechanisms of ectopic ossification and association of TSPCs are not yet known. Here, we investigated the characteristics of Prg4-positive (+) cells and identified that R-spondin 2 (RSPO2), a WNT activator, is specifically expressed in a distinct Prg4+ TSPC cluster. The Rspo2+ cluster was characterized as mostly undifferentiated, and RSPO2 overexpression suppressed ectopic ossification in a mouse Achilles tendon puncture model via chondrogenic differentiation suppression. RSPO2 expression levels in patients with ossification of the posterior longitudinal ligament were lower than those in spondylosis patients, and RSPO2 protein suppressed chondrogenic differentiation of human ligament cells. RSPO2 was induced by inflammatory stimulation and mechanical loading via nuclear factor κB. Rspo2+ cells may contribute to tendon/ligament homeostasis under pathogenic conditions.

Increasing trend of radiographic features of knee osteoarthritis in rheumatoid arthritis patients before total knee arthroplasty.

To investigate the trend and factors related to the occurrence of osteoarthritis (OA)-like features on knee radiographs of rheumatoid arthritis (RA) patients undergoing total knee arthroplasty (TKA) in the recent decades. To classify antero-posterior knee radiographs into 'RA' and 'OA-like RA' groups, a deep learning model was developed by training the network using knee radiographs of end-stage arthropathy in RA patients obtained during 2002-2005 and in primary OA patients obtained during 2007-2009. We used this model to categorize 796 knee radiographs, which were recorded in RA patients before TKA during 2006-2020, into 'OA-like RA' and 'RA' groups. The annual ratio of 'OA-like RA' was investigated. Moreover, univariate and multivariate analyses were performed to identify the factors associated with the classification as OA-like RA using clinical data from 240 patients. The percentage of 'OA-like RA' had significant increasing trend from 20.9% in 2006 to 67.7% in 2020. Higher body mass index, use of biologics, and lower level of C-reactive protein were identified as independent factors for 'OA-like RA'. An increasing trend of knee radiographs with OA-like features was observed in RA patients in the recent decades, which might be attributed to recent advances in pharmacotherapy.

The discrepancy between radiographically-assessed and self-recognized hallux valgus in a large population-based cohort.

BACKGROUND: There has been a paucity of literature revealing the discrepancy between self-recognition about hallux valgus (HV) and radiographically-evaluated foot configuration. Knowing this discrepancy will help to make a comparative review of the findings of previous literatures about epidemiological studies about the prevalence of HV. QUESTIONS/PURPOSES: (1) Is there a discrepancy between radiographically-assessed and self-recognized HV in the general population? (2) What factors affect the self-recognition of HV in the general population? METHODS: The fifth survey of the Research on Osteoarthritis/Osteoporosis against Disability study involved 1996 participants who had undergone anterior-posterior radiography of bilateral feet and answered a simple dichotomous questionnaire on self-recognition of HV. Measurements of the HV angle (HVA), interphalangeal angle of the hallux (IPA), and intermetatarsal angle between 1st and 2nd metatarsals (IMA) were performed using radiographs. Radiographic diagnosis of HV was done using the definition of hallux valgus angle of 20° or more. After univariate comparison of the participant backgrounds and radiographic measurements between participants with or without self-recognition of HV, multivariable logistic regression analysis was conducted in order to reveal independent factors affecting self-recognition. RESULTS: Significant difference was found between the prevalence of radiographically-assessed and self-recognized HV (29.8% vs. 16.5%, p <  0.0001). The prevalence of self-recognized HV increased with the progression of HV severity from a single-digit percentage (normal grade, HVA < 20°) up to 100% (severe grade, HVA ≥ 40°). A multivariable logistic regression analysis demonstrated that HVA, IMA, and female sex were independent positive factors for self-recognition of HV (HVA [per 1° increase]: OR, 1.18; 95% CI, 1.15-1.20; p <  0.0001; IMA [per 1° increase]: OR, 1.15; 95% CI, 1.09-1.20; p <  0.0001; and female sex [vs. male sex]: OR, 3.47; 95% CI, 2.35-5.18; p <  0.0001). CONCLUSIONS: There was a significant discrepancy between radiographically-assessed and self-recognized HV which narrowed with the progressing severity of HV. HVA, IMA, and female sex were independent positive factors for self-recognition of HV. Attention needs to be paid to potentially lowered prevalence of HV in epidemiological studies using self-reporting based on self-recognition.

Comparison between suture and staple fixations as internal fixation techniques for Akin osteotomy.

BACKGROUND: Suture and staple fixations are commonly used methods for Akin osteotomy; however, there has been a paucity of studies comparing these methods without bias. PATIENTS AND METHODS: We retrospectively compared the outcomes of 58 Akin osteotomies performed by a single surgeon using suture fixation and 39 Akin osteotomies performed by the same surgeon using staple fixation during the same period. RESULTS: Bone union at the osteotomy site was achieved in all cases with no cases of complications related to the materials used. Occurrence of breakage of the lateral cortex of the proximal phalanx showed no significant difference between the suture and staple groups. The lateral cortex breakage produced greater instability at the osteotomy site with the staple fixation compared to the suture fixation. CONCLUSIONS: Comparison of suture and staple fixations of Akin osteotomy demonstrated the superiority of suture fixation against staple fixation in terms of stability and cost-efficiency.

Symptomatic Medial Bone Excrescence in the Distal Phalanx of the Hallux after the First Metatarsophalangeal Joint Arthrodesis: A Case Report and Radiographic Reviews.

Medial bone excrescence at the base of the distal phalanx of the hallux is a common manifestation which is rarely painful. In this case report, we described the first case of the excrescence becoming symptomatic one year after a metatarsophalangeal (MTP) joint arthrodesis of the great toe in a 74-year-old female. The medial bony excrescence which was obscure preoperatively became obvious postoperatively in the anteroposterior foot radiographs. The patient was successfully treated by an excision of the excrescence. In order to clarify the pathology of the excrescence, we reviewed the radiographs with respect to the excrescence before and after hallux surgeries including 97 metatarsal osteotomies and 33 MTP joint arthrodesis. The width of the excrescence measured in the anteroposterior foot radiographs displayed substantial increment one month after the hallux surgeries (osteotomy group: 0.9 ± 0.7 vs. 1.5 ± 0.7 mm, p < 0.01; arthrodesis group: 1.3 ± 0.8 vs. 1.8 ± 1.0 mm, p < 0.01). However, there was no significant difference in the width of the excrescence between one month after surgery and at the most recent follow-up of around 20 months in average after the surgery (osteotomy group: 1.5 ± 0.7 vs. 1.4 ± 0.7 mm, p = 0.62; arthrodesis group: 1.8 ± 1.0 vs. 1.8 ± 0.7 mm, p = 0.37). The present case and our radiographic review suggested that the postoperative medial bony excrescence was not the result of change of position of the preexisting excrescence. The correction of pronation deformity through hallux surgeries could emphasize the medial bony excrescence and cause symptomatic irritation upon shoe contact.

Outcomes of Scarf and Akin Osteotomy with Intra-Articular Stepwise Lateral Soft Tissue Release for Correcting Hallux Valgus Deformity in Rheumatoid Arthritis.

BACKGROUND: The effectiveness of scarf and Akin osteotomy with intra-articular lateral soft tissue release for the correction of hallux valgus (HV) in patients with rheumatoid arthritis (RA) has not been elucidated. METHODS: A total of 36 feet in 28 patients with RA who had scarf and Akin osteotomy with intra-articular stepwise lateral soft tissue release between 2015 and 2020 at a single institute were investigated retrospectively, with a mean follow-up period of 32.0 ± 16.9 months. Radiographic evaluations including the HV angle, intermetatarsal angle, and sesamoid position were performed preoperatively and postoperatively. Clinical outcomes were assessed using the Japanese Society of Surgery of the Foot (JSSF) hallux scale and self-administered foot evaluation questionnaire (SAFE-Q). RESULTS: The procedure resulted in significant HV correction, with a recurrence rate of 13.9%. The JSSF scale and all five SAFE-Q subscale scores significantly improved (p < 0.05), with no major complications. More than 90% of cases achieved adequate lateral soft tissue release without sacrificing the adductor tendon of the hallux. CONCLUSIONS: Intra-articular stepwise lateral soft tissue release in combination with scarf and Akin osteotomy provided satisfactory radiographic and patient-reported outcomes for the correction of HV in patients with RA with minimum lateral soft tissue release.

Systemic inflammatory responses after orthopedic surgery in patients with rheumatoid arthritis treated with tofacitinib.

OBJECTIVE: To investigate the acute phase response to surgical stress in patients with rheumatoid arthritis (RA) treated with tofacitinib, a Janus kinase (JAK) inhibitor. METHODS: A retrospective matched pair analysis of 34 patients treated with tofacitinib and 34 patients treated with conventional disease-modifying anti-rheumatic drugs (csDMARDs) was performed. Patients were matched for age, sex, and type of surgery; body temperature, C-reactive protein (CRP) level, and white blood cell (WBC) count, neutrophil count, and lymphocyte count were compared between the tofacitinib and csDMARDs groups within 2 weeks after orthopedic surgery. Postoperative complications within 90 days were also assessed. RESULTS: No surgical site infection or delayed wound healing was observed in the tofacitinib group; whereas, one case of superficial infection was noted in the csDMARDs group. A similar postoperative increase in body temperature and CRP level was observed in both the groups. Postoperatively, the tofacitinib group showed an increase in WBC and neutrophils counts and a decrease in lymphocyte count, unlike the csDMARDs group. In contrast to two patients (2.6%) in the csDMARDs group, seven patients (20.6%) in the tofacitinib group had lymphocyte counts below 500 cells/µL within 2 weeks postoperatively. CONCLUSION: Tofacitinib did not suppress postoperative increase in body temperature and CRP level. Because of the postoperative decrease in lymphocyte count in patients treated with tofacitinib, the timing for resuming tofacitinib treatment after surgery should be carefully considered. Key Points • This study is the first to report the complications and systemic inflammatory responses after orthopedic surgery in patients treated with tofacitinib in comparison with matched pairs treated with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) • While tofacitinib does not suppress postoperative increase in body temperature and CRP level, the postoperative decrease in lymphocyte count in patients treated with tofacitinib is significant compared with patients treated with csDMARDs • Attention should be paid to a reduced lymphocyte count when to resume tofacitinib after surgery.

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.

Juvenile Dysplasia Epiphysealis Hemimelica with Multiple Ankle Free Body.

Dysplasia epiphysealis hemimelica (DEH), also known as Trevor's disease, is a rare overgrowth of cartilage that commonly arises in the epiphyseal bone of children. We report a rare case of DEH originating from a talus accompanied by multiple intra-articular free bodies in a 7-year-old patient with ankle instability. After the primary surgery for free body removal and microfracture technique for the cartilage defects in the ankle joint, the free body recurred. Secondary surgery of arthroscopic free body removal with lateral ankle ligament repair succeeded in treating the patient, without further recurrence of the free body.

Involvement of Transient Receptor Potential Vanilloid Channel 2 in the Induction of Lubricin and Suppression of Ectopic Endochondral Ossification in Mouse Articular Cartilage.

OBJECTIVE: Transient receptor potential vanilloid channel 2 (TRPV2) is a Ca2+ -permeable channel and plays a role in mediating intracellular Ca2+ current via mechanical stimuli. This study was undertaken to examine the expression and role of TRPV2 in adult articular cartilage and the development of osteoarthritis (OA). METHODS: We examined TRPV2 expression in mouse and human articular cartilage. We analyzed the development of OA in Col2a1-CreERt2 ;Trpv2fl/fl mice and Trpv2fl/fl littermates in the resection of the medial meniscus and medial collateral ligament model (n = 5 each), the destabilization of the medial meniscus model (n = 5 each), and the aging mouse model (n = 8-9 each). We examined marker protein expression in these joints, Ca2+ influx by mechanical stimuli, and downstream pathways in vitro. RESULTS: TRPV2 was expressed in mouse and human articular cartilage and ectopic ossification lesions. In all mouse models of OA examined, Col2a1-CreERt2 ;Trpv2fl/fl mice were observed to have enhanced degradation of articular cartilage accompanied by decreased expression of lubricin/Prg4, and marked formation of periarticular ectopic ossification. Mechanical stress-induced Ca2+ influx was decreased by Trpv2 knockout (KO). Prg4 induction by fluid-flow shear stress was diminished in Trpv2-KO mouse chondrocytes, and this was mediated by the Ca2+ /calmodulin-dependent protein kinase kinase-cyclic AMP response element binding protein axis. Hypertrophic differentiation was enhanced in Trpv2-KO mouse chondrocytes. Increased activity of calcineurin and nuclear translocation of nuclear factor in activated T cells 1 induced by fluid-flow shear stress or TRP agonist treatment was reversed by Trpv2 knockout. CONCLUSION: Our findings demonstrate regulation of articular cartilage by TRPV2 through Prg4 induction and suppression of ectopic ossification.

Lubricin Contributes to Homeostasis of Articular Cartilage by Modulating Differentiation of Superficial Zone Cells.

Lubricin encoded by the proteoglycan 4 (Prg4) gene is produced from superficial zone (SFZ) cells of articular cartilage and synoviocytes, which is indispensable for lubrication of joint surfaces. Loss-of-function of human and mouse Prg4 results in early-onset arthropathy accompanied by lost SFZ cells and hyperplastic synovium. Here, we focused on increases in the thickness of articular cartilage in Prg4-knockout joints and analyzed the underlying mechanisms. In the late stage of articular cartilage development, the articular cartilage was thickened at 2 to 4 weeks and the SFZ disappeared at 8 weeks in Prg4-knockout mice. Similar changes were observed in cultured Prg4-knockout femoral heads. Cell tracking showed that Prg4-knockout SFZ cells at 1 week of age expanded to deep layers after 1 week. In in vitro experiments, overexpression of Prg4 lacking a mucin-like domain suppressed differentiation of ATDC5 cells markedly, whereas pellets of Prg4-knockout SFZ cells showed enhanced differentiation. RNA sequencing identified matrix metalloproteinase 9 (Mmp9) as the top upregulated gene by Prg4 knockout. Mmp9 expressed in the SFZ was further induced in Prg4-knockout mice. The increased expression of Mmp9 by Prg4 knockout was canceled by IκB kinase (IKK) inhibitor treatment. Phosphorylation of Smad2 was also enhanced in Prg4-knockout cell pellets, which was canceled by the IKK inhibitor. Expression of Mmp9 and phosphorylated Smad2 during articular cartilage development was enhanced in Prg4-knockout joints. Lubricin contributes to homeostasis of articular cartilage by suppressing differentiation of SFZ cells, and the nuclear factor-kappa B-Mmp9-TGF-ß pathway is probably responsible for the downstream action of lubricin. © 2020 American Society for Bone and Mineral Research (ASBMR).

Associations of clinical outcomes and MRI findings in intra-articular administration of autologous adipose-derived stem cells for knee osteoarthritis.

INTRODUCTION: Clinical studies of intra-articular injection of mesenchymal stem cells for osteoarthritis (OA) indicate its efficacy. Here, we retrospectively investigated the associations of pretherapeutic magnetic resonance imaging (MRI) findings with the clinical outcomes up to 6 months, after intra-articular administration of adipose-derived stem cells (ASCs) to knee OA patients. METHODS: We first analyzed alterations of the visual analog scale (VAS) and knee injury and osteoarthritis outcome score (KOOS) in 57 knees of 34 patients from whom clinical scores were obtained before ASC therapy, and at 1, 3, and 6 months. Among the patients, we further examined MRI findings of 34 knees of 19 patients whose pretherapeutic MRI data were available. RESULTS: The mean improvement of VAS and KOOS-total during 6 months was 2.6 ± 4.0 (from 6.1 ± 2.5 to 3.5 ± 2.9, P < 0.001) and 10.2 ± 12.4 (from 54.4 ± 12.7 to 64.6 ± 13.8, P < 0.01), respectively. Scales related to pain and symptoms improved earlier than those related to activities of daily living (ADL) and sports/recreation. Improvement of VAS and KOOS-sports/recreation was significantly higher in patients with more severe cartilage lesions. Similarly, osteophyte lesions were associated significantly with improvement of VAS and KOOS-ADL, and BML was associated with KOOS-ADL and KOOS-sports/recreation. CONCLUSIONS: In intra-articular administration of autologous ASCs for knee OA, improvement of VAS and KOOS-sports/recreation was significantly higher in patients with more severe cartilage lesions. Similarly, osteophyte lesions were associated significantly with improvement of VAS and KOOS-ADL, and BML was associated with KOOS-ADL and KOOS-sports/recreation. Clinical studies with larger numbers of patients and various kinds of data are necessary to predict therapeutic effects.

Prolonged Myelosuppression due to Progressive Bone Marrow Fibrosis in a Patient with Acute Promyelocytic Leukemia.

A 34-year-old woman was diagnosed with acute promyelocytic leukemia. Chemotherapy was administered following the JALSG APL204 protocol. Induction therapy with all-trans retinoic acid resulted in complete remission on day 49. She developed coccygeal pain from day 18, which spread to the spine and cheekbones and lasted 5 weeks. She had similar bone pain on days 7-10 of the first consolidation therapy and on days 4-12 of the second consolidation therapy. Oral loxoprofen was prescribed for pain relief. On day 33 of the third consolidation, white blood cell and neutrophil counts were 320/µL and 20/µL, respectively. After she developed epigastralgia and hematemesis, she developed septic shock. Gastroendoscopy revealed markedly thickened folds and diffusely damaged mucosa with blood oozing. Computed tomography revealed thickened walls of the antrum and the pylorus. Despite emergency treatments, she died. Bacterial culture of the gastric fluid yielded Enterobacter cloacae and enterococci growth. Collectively, she was diagnosed with phlegmonous gastritis. Retrospective examination of serial bone marrow biopsy specimens demonstrated progressive bone marrow fibrosis, which may have caused prolonged myelosuppression. Thus, evaluation of bone marrow fibrosis by bone marrow biopsy after each treatment cycle might serve as a predictor of persistent myelosuppression induced by chemotherapy.

Wnt/ß-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone.

BACKGROUND: Both loss- and gain-of-function of Wnt/ß-catenin signaling in chondrocytes result in exacerbation of osteoarthritis (OA). Here, we examined the activity and roles of Wnt/ß-catenin signaling in the superficial zone (SFZ) of articular cartilage. METHODS: Wnt/ß-catenin signaling activity was analyzed using TOPGAL mice. We generated Prg4-CreERT2;Ctnnb1fl/fl and Prg4-CreERT2;Ctnnb1-ex3fl/wt mice for loss- and gain-of-function, respectively, of Wnt/ß-catenin signaling in the SFZ. Regulation of Prg4 expression by Wnt/ß-catenin signaling was examined in vitro, as were upstream and downstream factors of Wnt/ß-catenin signaling in SFZ cells. RESULTS: Wnt/ß-catenin signaling activity, as determined by the TOPGAL reporter, was high specifically in the SFZ of mouse adult articular cartilage, where Prg4 is abundantly expressed. In SFZ-specific ß-catenin-knockout mice, OA development was significantly accelerated, which was accompanied by decreased Prg4 expression and SFZ destruction. In contrast, Prg4 expression was enhanced and cartilage degeneration was suppressed in SFZ-specific ß-catenin-stabilized mice. In primary SFZ cells, Prg4 expression was downregulated by ß-catenin knockout, while it was upregulated by ß-catenin stabilization by exon 3 deletion or treatment with CHIR99021. Among Wnt ligands, Wnt5a, Wnt5b, and Wnt9a were highly expressed in SFZ cells, and recombinant human WNT5A and WNT5B stimulated Prg4 expression. Mechanical loading upregulated expression of these ligands and further promoted Prg4 transcription. Moreover, mechanical loading and Wnt/ß-catenin signaling activation increased mRNA levels of Creb1, a potent transcription factor for Prg4. CONCLUSIONS: We demonstrated that Wnt/ß-catenin signaling regulates Prg4 expression in the SFZ of mouse adult articular cartilage, which plays essential roles in the homeostasis of articular cartilage.

Oral administration of EP4-selective agonist KAG-308 suppresses mouse knee osteoarthritis development through reduction of chondrocyte hypertrophy and TNF secretion.

Osteoarthritis (OA) is one of the world's most common degenerative diseases, but there is no disease-modifying treatment available. Previous studies have shown that prostaglandin E2 (PGE2) and PGE2 receptor 4 (EP4) are involved in OA pathogenesis; however, their roles are not fully understood. Here, we examined the efficacy of oral administration of KAG-308, an EP4-selective agonist, in surgically induced mouse knee OA. Cartilage degeneration and synovitis were significantly inhibited by the KAG-308 treatment. Chondrocyte hypertrophy and expression of tumor necrosis factor alpha (TNF) and matrix metalloproteinase 13 (Mmp13) in the synovium were suppressed in the KAG-308-treated mice. In cultured chondrocytes, hypertrophic differentiation was inhibited by KAG-308 and intranuclear translocation of histone deacetylase 4 (Hdac4) was enhanced. In cultured synoviocytes, lipopolysaccharide (LPS)-induced expression of TNF and Mmp13 was also suppressed by KAG-308. KAG-308 was detected in the synovium and cartilage of orally treated mice. TNF secretion from the synovia of KAG-308-treated mice was significantly lower than control mice. Thus, we conclude that oral administration of KAG-308 suppresses OA development through suppression of chondrocyte hypertrophy and synovitis. KAG-308 may be a potent candidate for OA drug development.

Guideposts for Inserting Intercuneiform Joint Arthrodesis Screws: Analysis Using Multiplanar Reconstructed Computed Tomography.

Intercuneiform arthrodesis is often required for various midfoot pathologies; however, intercuneiform screw insertion is not easy due to the complicated anatomical structure of cuneiforms. This study aimed to determine the advisable screw entry point and direction using intraoperatively detectable landmarks. The computed tomography (CT) scan data of feet were reformatted using OsiriX software multiplanar reconstruction. First, based on the data of 10 CT scans of normal feet, we determined the advisable screw entry point at the upper one-third in the dorsoplantar direction and center in the anteroposterior direction on the medial aspect of the medial cuneiform and insertion direction toward the outermost point of the base of the fifth metatarsal in the axial plane and parallel to the plantar surface in the coronal plane. Second, we examined the accuracy of these newly designed guideposts in the simulation using other CT scan data of the other 27 normal feet and 12 flat feet. The simulated screw trajectory penetrated the mid three-fifths of all three cuneiforms in 97% of the normal feet and 92% of the flat feet with no cases of cortical wall violation. Levels of Evidence: Level V: Expert opinion.