Synovial-tissue resident macrophages play proinflammatory functions in the pathogenesis of RA while maintaining the phenotypes in the steady state.

Synovial tissue-resident macrophages (STRMs) maintain normal joint homeostasis in a steady state. However, it is unclear whether STRMs still play homeostatic roles or change the functions in the joint of rheumatoid arthritis (RA), where infiltrating peripheral blood monocyte-derived macrophages (PBMoMs) play proinflammatory roles. In the present study, we examined changes in the phenotypes and functions of STRMs in response to RA-related stimuli in vitro. STRMs were prepared from non-inflammatory osteoarthritis (OA) joint synovium, which is histologically indistinguishable from normal joint synovium. PBMoMs were prepared and used for comparison. After stimulation with plate-bound IgG, which mimics anti-citrullinated protein antibody immunocomplex formed in RA joints, or with combinations of RA-related inflammatory mediators, namely tumor necrosis factor-α (TNF-α) and prostaglandin E2 or interferon-γ, PBMoMs downregulated surface markers and genes associated with anti-inflammatory macrophages, and upregulated cytokine and marker genes of proinflammatory macrophages in RA. On the other hand, STRMs hardly changed the expression of surface molecules and marker genes but altered the pattern of cytokine gene expression after stimulation like PBMoMs. Furthermore, in vitro stimulated STRMs promote proinflammatory functions of cocultured synovial fibroblasts. Thus, STRMs might play proinflammatory roles in RA joints, while maintaining their phenotypes in the steady state.

Is there a reduction in hip destruction under a treat-to-target strategy in patients with rheumatoid arthritis?

OBJECTIVES: The treatments for rheumatoid arthritis (RA) have been greatly improved, and the tight control of disease activity yields superior clinical outcomes. This study aimed to elucidate the accompanying changes in hip destruction following the implementation of a treat-to-target strategy for patients with RA. METHODS: We extracted 190 hips over two periods, i.e. the early period (1998-2003) and the late period (2013-19), with 103 and 87 hips, respectively. The observed rheumatic changes, such as inward migration, upward migration, and femoral head collapse, were quantitatively evaluated, while osteoarthritic changes, such as the formation of a capital drop, were investigated from radiographs before primary total hip arthroplasty. RESULTS: A comparison of the two periods' data showed that the degree of inward migration (-3.44 vs. -7.45 mm; P < .001) and upward migration (+4.3 vs. +0.95 mm; P < .001) significantly decreased in the late-period group. The collapse of the femoral head was not significantly different. The incidence of capital drops was significantly higher in the late-period group (7.8% vs. 27.5%; P < .001). CONCLUSIONS: The degree of inward and upward migration representative of rheumatic changes reduced, whereas the frequency of capital drops as osteoarthritic changes increased during the late period.

Complications After Orthopedic Surgeries in Patients with Rheumatoid Arthritis Treated with Janus Kinase Inhibitors: a Retrospective Observational Study.

OBJECTIVES: The current study compared the outcome after orthopedic surgeries in patients with RA receiving JAKi versus biologic disease-modifying anti-rheumatic drugs (bDMARDs). METHODS: This was a retrospective observational study of Japanese patients with RA. Sixty-two patients with RA using JAKi preoperatively underwent orthopedic surgeries. Using propensity score matching, these 62 patients were matched with 62 patients using bDMARDs preoperatively. The number of adverse events was counted. We also examined whether the drug-withholding period in the JAKi-treated group was associated with the occurrence of major postoperative adverse events, namely inflammatory flares and delayed wound healing (DWH). RESULTS: JAKi-treated patients had a higher incidence of postoperative flares than bDMARDs-treated patients (29% vs 12.1%, p=0.01). The incidences of postoperative complications other than flares were not significantly different between the two groups. Among the JAKi-treated group, a longer perioperative drug-withholding period (≥11 days) was associated with a higher incidence of postoperative flares (p=0.04). The incidences of DWH and SSI were not associated with the duration of the JAKi withholding period. CONCLUSION: JAKi-treated patients had a higher incidence of postoperative flares than bDMARDs-treated patients. A total of 11 days or more of drug withdrawal was associated with postoperative flares.

Interaction between functional capability and sleep quality at midterm after total knee arthroplasty: a Japanese retrospective cohort study.

No report has clarified the frequency and interacting factors affecting sleep disturbance among Asian patients at midterm after total knee arthroplasty (TKA). This study aimed to evaluate the frequency of sleep disturbance at midterm after TKA in a Japanese cohort and to identify intervening factors for sleep. We hypothesized that residual knee pain and decreased functional capability negatively interact with sleep quality after TKA. A total of 209 Japanese participants (average age: 77.1 ± 8.3 years; postoperative follow-up period: 4.5 ± 1.9 years) who underwent primary TKA for knee osteoarthritis were included in this study. Sleep quality, satisfaction, pain, functional capability, joint awareness, and mental condition were evaluated using the Pittsburgh Sleep Quality Index (PSQI), Knee Society Score (KSS) 2011, Forgotten Joint Score (FJS)-12, and 12-Item Short-Form Health Survey (SF-12) Mental Component Summary (MCS). Multivariable analysis was performed to determine the influencing factors on PSQI. The scores for the PSQI, satisfaction with pain level while lying in bed, pain during level walking, functional activity category in the KSS 2011, awareness of the artificial joint in bed at night in the FJS-12, and SF-12 MCS were 6.7 ± 3.0, 5.8 ± 1.8, 1.6 ± 2.3, 62 ± 22, 1.5 ± 1.4, and 56 ± 9.3 on average, respectively. Sleep disturbance (PSQI ≥ 5.5) occurred in 54% of the Japanese participants. Multivariable analysis revealed that high functional capability was a significant factor associated with sleep quality improvement (p < 0.05). Decreased functional capability, not residual knee pain, negatively interacted with sleep quality. The sleep disturbance rate was high during the middle postoperative period after TKA in the Japanese cohort.

Arthroscopic Treatment of Septic Arthritis of the Ankle Caused by Group B Streptococcus: A Case Report.

BACKGROUND The incidence of septic arthritis of a native joint caused by group B streptococcus (GBS, Streptococcus agalactiae) has been on the rise in non-pregnant women. GBS commonly colonizes the female genital tract. However, only a few reports have discussed serious cases of GBS infection, endocarditis, and joint infection associated with the Papanicolaou (Pap) smear test, which is routinely conducted to detect cervical cancer. Specifically, to the best of our knowledge, there have been few reports about arthroscopic treatment for septic arthritis of the ankle caused by GBS. CASE REPORT A 60-year-old woman, who had previously completed the treatment of total laparoscopic hysterectomy with bilateral adnexectomy and postoperative chemotherapy for ovarian cancer, underwent a routine Pap smear test. Four weeks later, she suddenly presented with high fever and abdominal pain. The pain and swelling in her left ankle gradually worsened. Finally, septic arthritis of the ankle was diagnosed, and thus the patient underwent emergent arthroscopic irrigation and debridement. GBS was isolated from both the ankle fluid and blood culture. After surgical intervention and intravenous antibiotic administration, the patient's symptoms gradually improved. Four months later, the patient had no ankle pain or restriction of ankle motion. CONCLUSIONS Although cervical cytology tests are essential in screening for cervical cancer, transient bacteremia can be induced by the tests. Thus, physicians must watch out for the development of septic arthritis caused by GBS when patients present with fever or swollen joints after a recent Pap smear test. Emergent diagnosis and appropriate surgical intervention is also important.

"Grand-piano sign" as a femoral rotational indicator in both varus and valgus knees: a simulation study of anterior resection surface in total knee arthroplasty.

PURPOSE: The "Grand-piano sign" is a popular indicator of the appropriate rotational alignment of the femoral component during total knee arthroplasty (TKA). The aim of the study was to investigate the shape of the anterior femoral resection surface of varus and valgus knees. METHODS: A cohort of 80 varus knees and 40 valgus knees (hip-knee-ankle angle > 2° for varus and < - 2° for valgus knees) matched for age, sex, height, body weight, and KL grade was made using propensity score matching. Virtual TKA was performed using 3 patterns of components (anterior flange flexion angles of 3°, 5°, and 7°). The anterior femoral resection surface was evaluated for 3 patterns of rotational alignments: parallel to the surgical epicondylar axis (NR, neutral rotation), 3° internal rotation (IR), and 3°external rotation (ER) relative to the surgical epicondylar axis. In each anterior femoral resection surface, the vertical height of medial and lateral condyles was measured, and the ratio of the medial to the lateral height (M/L ratio) was evaluated. RESULTS: The M/L ratio in NR for both varus and valgus knees was 0.57 to 0.64, with no significant difference between the cohorts (p value > 0.05). The M/L ratio showed a similar pattern of increasing at IR and decreasing at ER in both varus and valgus knees. The variation in the M/L ratio with malrotation in valgus knees was smaller than in varus knees. CONCLUSION: During TKA, the anterior femoral resection surface was similar in varus and valgus knees; however, the variation with malrotation was smaller in valgus knees than in varus knees. TKA for valgus knees requires precise surgical technique and careful intraoperative assessment. LEVEL OF EVIDENCE: IV, Case series.

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. Gain- or loss-of-function experiments were performed using human chondrocytes. Furthermore, OA was surgically induced in mice, followed by intraarticular injection of BAY-985, an IKKε/TANK-binding kinase 1 inhibitor, into the left knee joint every 5 days for 8 weeks. Mice were subsequently examined for histologic features of cartilage damage and inflammation. RESULTS: IKKε protein expression was increased in human OA cartilage. In vitro, expression levels of OA-related factors were down-regulated following knockdown of IKKε with the use of small interfering RNA in human OA chondrocytes or following treatment with BAY-985. Conversely, IKKε overexpression significantly increased the expression of OA-related catabolic mediators. In Western blot analysis of human chondrocytes, IKKε overexpression increased the phosphorylation of IκBα and p65. In vivo, intraarticular injection of BAY-985 into the knee joints of mice attenuated OA-related cartilage degradation and hyperalgesia via NF-κB signaling. CONCLUSION: These results suggest that IKKε regulates cartilage degradation through a catabolic response mediated by NF-κB signaling, and this could represent a potential target for OA treatment. Furthermore, BAY-985 may serve as a major disease-modifying compound among the drugs developed for OA.

Steroid-induced osteonecrosis of the humeral head in a 20-year-old man treated with an osteochondral autograft: A case report.

To our knowledge, only one previous report described the treatment of osteochondral autograft for steroid-induced osteonecrosis of the humeral head (ONHH) in a middle-aged patient. The present report describes a 20-year-old man who was found to have avascular osteonecrosis of the right humeral head after corticosteroid pulse treatment, followed by oral corticosteroid therapy. The patient complained of serious right shoulder pain and limited range of motion (ROM). Anteroposterior (AP) radiographs of the right shoulder revealed a crescent sign at the humeral head, indicating subchondral bone collapse with a linear sclerotic change and normal articular surface of the glenoid. The case was categorized as Stage 3 according to the Cruess classification. In general, Cruess classification Stage 3 is treated with humeral head replacement and shoulder arthroplasty. The patient underwent surgical treatment involving osteochondral autograft transplantation. Autografts were harvested from the right knee. At the 1.5-year follow-up, the patient was pain-free and showed an improved active ROM. Furthermore, AP radiographs demonstrated that the glenohumeral joint space was maintained, and no progression of humeral head collapse was observed. This case may be helpful in decision-making if young patients with ONHH require surgical treatment. Furthermore, osteochondral autograft transplantation may be an effective treatment for ONHH.

Similar short-term KOOS between open-wedge high tibial osteotomy and total knee arthroplasty in patients over age 60: A propensity score-matched cohort study.

OBJECTIVES: The purpose of the present study was to evaluate improvement in the Knee Injury and Osteoarthritis Outcome Score (KOOS) after open-wedge high tibial osteotomy (HTO) in comparison with total knee arthroplasty (TKA) in cohorts over age 60 matched by pre-operative age, gender, body mass index (BMI), hip-knee-ankle angle (HKAA), KOOS sub-scores, and osteoarthritis (OA) grade. METHODS: Propensity score matching was performed between 162 HTO patients and 134 TKA patients. When calculating the propensity score by multivariate logistic regression analysis, the following pre-operative confounders were included: age, gender, BMI, HKAA, KOOS sub-scores, and OA grade. Consequently, a total of 55 patients were included in each group. The Student's t-test was used to analyse differences in the post-operative KOOS sub-scores between groups. RESULTS: After propensity score matching, all matched pre-operative valuables were identical, with no significant differences between the HTO and TKA groups. None of the post-operative KOOS sub-scores at 1 year after surgery showed a significant difference between the HTO and TKA groups. Both groups demonstrated significant and comparable post-operative improvement in every KOOS sub-score. CONCLUSIONS: In patients over age 60, there was no significant difference in short-term pain relief and improvements in activity and quality of life between HTO and TKA after propensity score matching including pre-operative age, KOOS sub-scores, and OA grade. HTO is a joint preservation procedure that is valid for knee OA even in individuals over age 60.

Fluvastatin promotes chondrogenic differentiation of adipose-derived mesenchymal stem cells by inducing bone morphogenetic protein 2.

BACKGROUND: Adipose-derived mesenchymal stem cells (ADMSCs) are a promising source of material source for medical regeneration of cartilage. Growth factors, including transforming growth factor-ß (TGFß) subfamily members and bone morphogenetic proteins (BMPs), play important roles in inducing and promoting chondrogenic differentiation of MSCs. However, these exogenous growth factors have some drawbacks related to their cost, biological half-life, and safety for clinical application. Several studies have reported that statins, the competitive inhibitors of 3-hydroxy-2-methylglutaryl coenzyme A (HMG-CoA) reductase, induce the expression of BMP2 in multiple cell types as the pleotropic effects. The objective of this study was to investigate the effects of fluvastatin during chondrogenic differentiation of human ADMSCs (hADMSCs). METHODS: The effects of fluvastatin were analyzed during chondrogenic differentiation of hADMSCs in the pellet culture without exogenous growth factors by qRT-PCR and histology. For functional studies, Noggin, an antagonist of BMPs, mevalonic acid (MVA) and geranylgeranyl pyrophosphate (GGPP), metabolites of the mevalonate pathway, ROCK inhibitor (Y27632), or RAC1 inhibitor (NSC23766) were applied to cells during chondrogenic differentiation. Furthermore, RhoA activity was measured by RhoA pulldown assay during chondrogenic differentiation with or without fluvastatin. Statistically significant differences between groups were determined by Student's t-test or the Tukey-Kramer test. RESULTS: Fluvastatin-treated cells expressed higher levels of BMP2, SOX9, ACAN, and COL2A1 than control cells, and accumulated higher levels of glycosaminoglycans (GAGs). Noggin significantly inhibited the fluvastatin-mediated upregulation of ACAN and COL2A1. Both MVA and GGPP suppressed the effects of fluvastatin on the expressions of BMP2, SOX9, ACAN, and COL2A1. Furthermore, fluvastatin suppressed the RhoA activity, and inhibition of RhoA-ROCK signaling by Y27632 increased the expressions of BMP2, SOX9, ACAN, and COL2A1, as well as fluvastatin. CONCLUSIONS: Our results suggest that fluvastatin promotes chondrogenic differentiation of hADMSCs by inducing endogenous BMP2, and that one of the mechanisms underlying the effects is inhibition of RhoA-ROCK signaling via suppression of GGPP. Fluvastatin is a safe and low-cost compound that holds promise for use in transplantation of hADMSCs for cartilage regeneration.

Preoperative Virtual Total Knee Arthroplasty Surgery Using a Computed Tomography-based 3-dimensional Model With Variation in Reference Points and Target Alignment to Predict Femoral Component Sizing.

Background: The purpose of this study was to investigate the size differences of 19 different femoral component placements from the standard position in total knee arthroplasty using 3-dimensional virtual surgery. Methods: Three-dimensional bone models were reconstructed from the computed tomography data of 101 varus osteoarthritic knees. The distal femoral bone was cut perpendicular to the femoral mechanical axis (MA) in the coronal plane. Twenty different component placements consisting of 5 cutting directions (perpendicular to MA, 3° and 5° extension relative to MA [3°E-MA and 5°E-MA, respectively], and 3° and 5° flexion relative to MA [3°F-MA and 5°F-MA, respectively]) in the sagittal plane, 2 rotational alignments (clinical epicondylar axis [CEA] and surgical epicondylar axis [SEA]), and 2 rotational types of anterior reference guide (central [CR] and medial [MR]) were simulated. Results: The mean anteroposterior dimension of femur ranged from 54.3 mm (5°F-MA, SEA, CR) to 62.5 mm (5°E-MA, CEA, MR). The largest and smallest differences of anteroposterior dimension from the standard position (3°F-MA, SEA, and CR) were 7.1 ± 1.3 mm (5°E-MA, CEA, and MR) and -1.2 ± 0.2 mm (5°F-MA, SEA, and CR), respectively. Multiple regression analysis revealed that flexion cutting direction, SEA, and CR were associated with smaller component size. Conclusions: The femoral component size can be affected easily by not only cutting direction but also the reference guide type and the target alignment. Our findings could provide surgeons with clinically useful information to fine-tune for unintended loose or tight joint gaps by adjusting the component size.

Sagittal femoral bowing contributes to distal femoral valgus angle deviation in malrotated preoperative radiographs.

BACKGROUND: The coronal whole-leg radiograph is generally used for preoperative planning in total knee arthroplasty. The distal femoral valgus angle (DFVA) is measured for distal femoral bone resection using an intramedullary guide rod. The effect of coronal and sagittal femoral shaft bowing on DFVA measurement in the presence of malrotation or knee flexion contracture has not been well reported. The objectives of this study were: (1) to investigate the effects of whole-leg malrotation and knee flexion contracture on the DFVA in detail, (2) to determine the additional effect of coronal or sagittal femoral shaft bowing. METHODS: We studied 100 consecutive varus and 100 valgus knees that underwent total or unicompartmental knee arthroplasty. Preoperative CT scans were used to create digitally reconstructed radiography (DRR) images in neutral rotation (NR, parallel to the surgical epicondylar axis), and at 5° and 10° external rotation (ER) and internal rotation (IR). The images were also reconstructed at 10° femoral flexion. The DFVA was evaluated in each DRR image, and the angular variation due to lower limb malposition was investigated. RESULTS: The DFVA increased as the DRR image shifted from IR to ER, and all angles increased further from extension to 10° flexion. The DFVA variation in each position was 1.3° on average. A larger variation than 2° was seen in 12% of all. Multivariate regression analysis showed that sagittal femoral shaft bowing was independently associated with a large variation of DFVA. Receiver operating characteristic analysis showed that more than 12° of sagittal bowing caused the variation. CONCLUSION: If femoral sagittal bowing is more than 12°, close attention should be paid to the lower limb position when taking whole-leg radiographs. Preoperative planning with whole-leg CT data should be considered.

Improved surgical procedure of primary constrained total knee arthroplasty which enables use of the femoral diaphyseal straight extension stem.

BACKGROUND: In performing primary constrained total knee arthroplasties (TKA) to imbalanced knees, the offset stem is sometimes compelled to use, although this is associated with surgical difficulties. We developed a modified procedure which might be able to fit the anteroposterior (AP) and mediolateral (ML) position of the femoral component simultaneously with the straight stem. Purposes of this study were to evaluate usefulness of the modified procedure both in computer simulations and actual surgeries. METHODS: We included 32 knees that had undergone primary TKA using constrained implants because of the coronal imbalance. In the component-first procedure, the distal femur was prepared to fit the AP and ML position of the femoral component simultaneously at first, as in primary TKA. Finally, the stem hole is created based on the femoral component position (the component-first procedure). The femoral component and extension stem were simulated using the three-dimensional planning software (ZedKnee) following the component-first procedure. We investigated the suitability of the straight stem through computer simulation and evaluation of actual surgeries. Clinical and radiographical outcomes were also evaluated at the latest follow-up. RESULTS: The component-first procedure enabled the AP and ML position of the femoral component to be fitted simultaneously with the straight stem in simulations and actual surgeries in all cases. The stem diameter was not significantly different between simulations and actual surgeries (13.9 and 13.7 mm on average, respectively, p = 0.479) and almost similar from intraclass correlation coefficient analysis (kappa value 0.790). Clinical and radiographical outcomes were almost similar to primary TKA cases and there was no case of component loosening, cortical bone hypertrophy around the stem and stem-tip pain. CONCLUSIONS: Our improved surgical procedure may facilitate use of the constrained implant for more cases of primary TKA in imbalanced knees without the usual surgical difficulties. TRIAL REGISTRATION: Retrospectively registered.

Smaller femoral neck anteversion in varus knees than in healthy and valgus knees.

It is important to investigate anatomical differences of the femur and tibia three-dimensionally between varus and valgus knees to enhance surgical approaches and better understand structural factors related to specific patterns of osteoarthritis progression. Three-dimensional femoral and tibial bone models were reconstructed from transverse computed-tomography scans in varus osteoarthritis (43 knees), valgus osteoarthritis (40 knees), and healthy (32 knees) groups. Different coordinate systems were defined in each femoral bone model ("Knee" and "Hip" Coordinate System). Femoral neck inclination, lateral bowing, anterior bowing, and neck anteversion were measured and compared between knee and hip coordinate systems. Those parameters were also compared between varus, valgus, and healthy groups. The tibial anterior and lateral bowing, external torsion and the fibular axis relative to the tibial mechanical axis were measured and compared between varus and valgus groups. Femoral neck anteversion was significantly 1-2° greater in the hip coordinate system compared to the knee coordinate system. Femoral neck anteversion was significantly smaller in varus knees than in healthy or valgus knees, with average difference of approximately 5°. The knee and hip joint are often rotated externally relative to the trunk axis in patients with varus osteoarthritis, perhaps maintaining the geometric relations between pelvis and proximal femur (including peripheral hip muscles) regardless of knee deformities. The fibular axis was inclined slightly valgus and posteriorly in two groups. The results may inform hypotheses on, and future studies of, skeletal morphologic development and factors contributing to the progression of knee osteoarthritis.

Factors affecting patient satisfaction related to cost and treatment effectiveness in rheumatoid arthritis: results from the multicenter observational cohort study, FRANK Registry.

BACKGROUND: To further improve rheumatoid arthritis (RA) treatment, it is necessary to understand each RA patient's satisfaction and to identify the factors affecting their satisfaction. Despite the rise in medical costs for RA, little is known about the factors that influence patient satisfaction with the cost of treatment in RA patients. METHODS: This is a multicenter observational study of Japanese RA patients from the FRANK Registry with data analyzed from March 2017 to August 2020. We collected data on demographic characteristics, clinical data, quality of life which was evaluated using the EuroQol 5-dimensional questionnaire (EQ5D), and patient satisfaction. The four categories of patient satisfaction were evaluated individually (i.e., cost, treatment efficacy, activities of daily living [ADL], and global treatment satisfaction). We analyzed the factors that affected each patient's satisfaction, such as age, sex, EQ5D, disease duration, disease activity, and treatment. RESULTS: This study included 2235 RA outpatients (406 males, 1829 females). In RA patients, "very satisfied" and "satisfied" were given for nearly half of each satisfaction aspect (cost 49%; efficacy 72%; ADL 58%; global treatment 66%) at the time of the initial registration. To investigate the factors influencing each satisfaction, multivariate analysis has revealed that the use of b/tsDMARDs increased satisfaction of treatment effect (odds ratio [OR] 0.66) and ADL (OR 0.78) but decreased cost satisfaction (OR 2.21). Age (50-64 years; OR 0.91; 65-74 years, 0.55: ≥ 75 years, 0.35), female (OR 0.81), and history of musculoskeletal surgery (OR 0.60) all increased cost satisfaction. Patients with lower disease activity and higher EQ5D scores had higher levels of satisfaction in all areas. CONCLUSIONS: In this study, patient satisfaction in terms of cost, treatment effect, ADL, and overall treatment was generally higher, but some patients were dissatisfied. The cost of satisfaction increased with age and a history of musculoskeletal surgery, while it decreased with a lower EQ5D score and the use of b/tsDMARDs.

Distinct Roles of Glutamine Metabolism in Benign and Malignant Cartilage Tumors With IDH Mutations.

Enchondromas and chondrosarcomas are common cartilage neoplasms that are either benign or malignant, respectively. The majority of these tumors harbor mutations in either IDH1 or IDH2. Glutamine metabolism has been implicated as a critical regulator of tumors with IDH mutations. Using genetic and pharmacological approaches, we demonstrated that glutaminase-mediated glutamine metabolism played distinct roles in enchondromas and chondrosarcomas with IDH1 or IDH2 mutations. Glutamine affected cell differentiation and viability in these tumors differently through different downstream metabolites. During murine enchondroma-like lesion development, glutamine-derived α-ketoglutarate promoted hypertrophic chondrocyte differentiation and regulated chondrocyte proliferation. Deletion of glutaminase in chondrocytes with Idh1 mutation increased the number and size of enchondroma-like lesions. In contrast, pharmacological inhibition of glutaminase in chondrosarcoma xenografts reduced overall tumor burden partially because glutamine-derived non-essential amino acids played an important role in preventing cell apoptosis. This study demonstrates that glutamine metabolism plays different roles in tumor initiation and cancer maintenance. Supplementation of α-ketoglutarate and inhibiting GLS may provide a therapeutic approach to suppress enchondroma and chondrosarcoma tumor growth, respectively. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

C10orf10/DEPP activates mitochondrial autophagy and maintains chondrocyte viability in the pathogenesis of osteoarthritis.

Osteoarthritis (OA), the most prevalent joint disease, is characterized by the progressive loss of articular cartilage. Autophagy, a lysosomal degradation pathway, maintains cellular homeostasis, and autophagic dysfunction in chondrocytes is a hallmark of OA pathogenesis. However, the cause of autophagic dysfunction in OA chondrocytes remains incompletely understood. Recent studies have reported that decidual protein induced by progesterone (C10orf10/DEPP) positively regulates autophagic functions. In this study, we found that DEPP was involved in mitochondrial autophagic functions of chondrocytes, as well as in OA pathogenesis. DEPP expression decreased in human OA chondrocytes in the absence or presence of pro-inflammatory cytokines, and was induced by starvation, hydrogen peroxide (H2 O2 ), and hypoxia (cobalt chloride). For functional studies, DEPP knockdown decreased autophagic flux induced by H2 O2 , whereas DEPP overexpression increased autophagic flux and maintained cell viability following H2 O2 treatment. DEPP was downregulated by knockdown of forkhead box class O (FOXO) transcription factors and modulated the autophagic function regulated by FOXO3. In an OA mouse model by destabilization of the medial meniscus, DEPP-knockout mice exacerbated the progression of cartilage degradation with TUNEL-positive cells, and chondrocytes isolated from knockout mice were decreased autophagic flux and increased cell death following H2 O2 treatment. Subcellular fractionation analysis revealed that mitochondria-located DEPP activated mitochondrial autophagy via BCL2 interacting protein 3. Taken together, our data demonstrate that DEPP is a major stress-inducible gene involved in the activation of mitochondrial autophagy in chondrocytes, and maintains chondrocyte viability during OA pathogenesis. DEPP represents a potential therapeutic target for enhancing autophagy in patients with OA.

Angular accuracy of plain radiographic measurements in leg alignment: Teleoroentgenogram versus orthoroentgenogram.

BACKGROUND: The purpose of the present study was to evaluate the accuracy of the measurements associated with leg alignment on a teleoroentgenogram and an orthoroentgenogram. METHODS: The models being irradiated were manufactured and represented 10° varus and 15° varus leg alignment, in which the true values of hip-knee-ankle angle (HKAA), mechanical axis (MA) length, and percentage of MA (%MA) were already known. HKAA, MA length, and %MA were measured in various radiographic conditions of the teleoroentgenogram and orthoroentgenogram. Then, the differences between the radiographic measurement values and the corresponding true values were analyzed. RESULTS: Regarding HKAA, the teleoroentgenogram provided accurate angular measurements with minimal differences between the measurement and true value in both the 10° and 15° varus models, irrespective of the radiographic condition. In the orthoroentgenogram, the modified method measured accurate HKAA; however, the standard method showed significant angular measurement errors with a 0.6° and 1.0° difference from the true value in the 10° and 15° varus models, respectively. This angular measurement error of HKAA in the standard orthoroentgenogram became significantly larger with object-to-image distance. Regarding MA length, the orthoroentgenogram exhibited accurate length measurements. In contrast, the teleoroentgenogram showed a significant length measurement error for the MA length. Regarding %MA, significant differences from the true values of 2.0% and 2.4% were observed in the modified orthoroentgenograms of the 10° and 15° varus models, respectively. The teleoroentgenogram and standard orthoroentgenogram reproduced the accurate measurement value of %MA in the 10° and 15° varus models. CONCLUSION: A teleoroentgenogram is a reliable modality for accurate angular measurements such as HKAA and %MA. An orthoroentgenogram has the potential to measure both HKAA and length accurately if the radiographic condition was modified; however, measurement error in %MA may occur.

Transverse osteotomy closer to tibial plateau is associated with larger postoperative change in valgus laxity after open-wedge high tibial osteotomy.

PURPOSE: To identify the factors impacting changes in valgus laxity between before and after open-wedge high tibial osteotomy (OW-HTO) using quantitative valgus stress radiographs. METHODS: A total of 40 knees from 38 patients who underwent OW-HTO were assessed. The study population comprised 14 men and 24 women, with a mean age of 61.5 years. Valgus stress radiographs before and 1 year after OW-HTO were performed using a Telos device. The difference between pre- and postoperative joint line convergence angle (JLCA) was expressed as ΔJLCA (post-pre). As indicators of the proximal detachment of superficial medial collateral ligament (sMCL) on radiographs, two distances were defined: the distance from the level of the osteotomy starting point to the tangent line of the proximal tibial plateau (Distance A), or to the medial edge of the proximal tibial plateau (Distance B). Correlations between ΔJLCA and radiographic parameters or KOOS sub-scores were assessed using Spearman's rank correlation coefficient analysis. Receiver operator curves were generated to evaluate the predictive strength of the significant factor for an increase in ΔJLCA > 1°. RESULTS: Pre-operative OA severity consisted of Kellgren-Lawrence grade 2 (n = 18), 3 (n = 16), and 4 (n = 6). The average ΔJLCA (post-pre) was 0.5°, and ranged from - 1.4° to + 3.0°. The maximum systemic measurement error and limits of agreement were 0.07° and 0.20°, respectively. There were significant correlations between ΔJLCA and Distance A (36.9 ± 3.9 mm, R = - 0.46, p = 0.002), between ΔJLCA and Distance B (39.9 ± 4.0 mm, R = - 0.49, p = 0.001). The cut-off value for Distance A was determined to be 35 mm below the tibial plateau; the AUC was 0.804, with a sensitivity of 0.75 and a specificity of 0.82. Distance B correlated strongly with Distance A (R = 0.96, p < 0.001). There was no significant correlation between ΔJLCA and KOOS sub-scores 1 year after OW-HTO. CONCLUSIONS: Transverse osteotomy closer to tibial plateau was associated with larger valgus joint laxity postoperatively. This finding implies that sMCL proximal detachment, which was related to the level of the osteotomy starting point on the proximal tibia, potentially affected postoperative valgus laxity. LEVEL OF EVIDENCE: IV.

Frequency and risk factor analyses of bone erosion of the distal interphalangeal joint in patients with rheumatoid arthritis: a cross-sectional study.

AIMS: Few reports have focused on the distal interphalangeal (DIP) joint in patients with rheumatoid arthritis (RA). The purposes of this study were to evaluate the frequency of bone erosion of the DIP joint, and to determine the factors associated with its deformity. METHODS: This study reviewed 204 patients with RA in whom radiographs of hands were obtained. According to the presence/absence of bone erosion of the DIP joint, patients were divided into two groups (DIP-positive and DIP-negative groups). Additionally, wrist, metacarpal phalangeal (MP), thumb interphalangeal (IP), and proximal interphalangeal (PIP) joints were evaluated. Clinical variables such as age, sex, body mass index, disease duration, disease activity (DAS28-CRP), and drug use were investigated. RESULTS: Regarding the radiological findings of the DIP joint, 32 patients (15.7%) were allocated to the DIP-positive group and 172 patients (84.3%) to the DIP-negative group. The mean age, disease duration, DAS28-CRP, and the rate of corticosteroids usage were significantly higher in the DIP-positive than in the DIP-negative group (p = 0.0031, 0.0062, 0.0342, and 0.0011, respectively). Radiologically, concomitant bone erosions of the wrist, MP, thumb IP, and PIP joints were significantly more common in the DIP-positive than in the DIP-negative group (p < 0.01 for all four joints). Multivariate analysis demonstrated that advanced age, long disease duration, and the presence of radiological bone erosion of the PIP joint were independently associated with bone erosion of the DIP joint (p = 0.0480, 0.0307, and 0.0021, respectively). Accordingly, in patients with DIP erosions, mean DAS28-CRP was significantly higher in patients with <5 years (n = 10) than in those with ≥5 years of disease duration (n = 22, p = 0.0088). CONCLUSIONS: Bone erosion can be observed at the DIP joint in patients with RA, and these cases frequently shows bone erosions of other finger joints, such as PIP joint. In addition, bone erosion can be observed soon after the onset of RA caused by uncontrolled disease activity in some patients with RA.