Automatic estimation of hallux valgus angle using deep neural network with axis-based annotation.

OBJECTIVES: We developed the deep neural network (DNN) model to automatically measure hallux valgus angle (HVA) and intermetatarsal angle (IMA) on foot radiographs. The objective is to assess the accuracy of the model by comparing to the manual measurement of foot and ankle surgeons. MATERIALS AND METHODS: A DNN was developed to predict the bone axes of the first proximal phalanx and all metatarsals from the first to the fifth in foot radiographs. The dataset used for model development consisted of 1798 radiographs collected from a population-based cohort and patients at our foot and ankle clinic. The retrospective validation cohort comprised of 92 radiographs obtained from 92 consecutive patients visiting our foot and ankle clinic. The mean absolute error (MAE) between automatic measurements by the model and the median of manual measurements by three foot and ankle surgeons was compared to 3° using one-tailed t-test and was also compared to the inter-rater difference in manual measurements among the three surgeons using two-tailed paired t-test. RESULTS: The MAE for HVA was 1.3° (upper limit of 95% CI 1.6°), and this was significantly smaller than the inter-rater difference of 2.0 ± 0.2° among the surgeons, demonstrating the superior accuracy of the model. In contrast, the MAE for IMA was 0.8° (upper limit of 95% CI 1.0°) that showed no significant difference from the inter-rater difference of 1.0 ± 0.1° among the surgeons. CONCLUSION: Our model demonstrated the ability to measure the HVA and IMA with an accuracy comparable to that of specialists.

Transcriptional reprogramming during human osteoclast differentiation identifies regulators of osteoclast activity.

Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis, which is characterized by increased bone resorption and inadequate bone formation. As novel antiosteoporotic therapeutics are needed, understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets. This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation. Osteoclasts were differentiated from CD14+ monocytes from eight female donors. RNA sequencing during differentiation revealed 8 980 differentially expressed genes grouped into eight temporal patterns conserved across donors. These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs. Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks. The donor-specific expression patterns revealed genes at the monocyte stage, such as filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1, encoding LOX-1), that are predictive of the resorptive activity of mature osteoclasts. The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation, and these receptors are associated with bone mineral density SNPs, suggesting that they play a pivotal role in osteoclast differentiation and activity. The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1 (C5AR1), somatostatin receptor 2 (SSTR2), and free fatty acid receptor 4 (FFAR4/GPR120). Activating C5AR1 enhanced osteoclast formation, while activating SSTR2 decreased the resorptive activity of mature osteoclasts, and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts. In conclusion, we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity. These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.

Changes in knee joint destruction patterns among patients with rheumatoid arthritis undergoing total knee arthroplasty in recent decades.

OBJECTIVES: This study aimed to investigate the trend of joint destruction patterns on knee radiographs of patients with rheumatoid arthritis (RA) undergoing total knee arthroplasty (TKA) over the past 16 years. METHOD: Medial joint space, lateral joint space, medial spur area, lateral spur area (L-spur), and femoro-tibial angle were obtained from 831 preoperative knee radiographs of patients with RA who underwent TKA between 2006 and 2021 using software capable of automatic measurements. Non-hierarchical clustering was performed based on these five parameters. Trends in the five individual radiographic parameters and the ratio of each cluster were investigated during the target period. Moreover, clinical data from 244 cases were compared among clusters to identify factors associated with this trend. RESULTS: All parameters, except for L-spur, showed significant increasing trends from 2006 to 2021. The radiographs were clustered into groups according to the characteristic pattern of radiographic findings: cluster 1 (conventional RA type), with bicompartmental joint space narrowing (JSN), less spur formation, and valgus alignment; cluster 2 (osteoarthritis type), with medial JSN, medial osteophytes, and varus alignment; and cluster 3 (less destructive type), with mild bicompartmental JSN, less spur formation, and valgus alignment. The ratio of cluster 1 showed a significantly decreasing trend contrary to the significantly increasing trend in clusters 2 and 3. The DAS28-CRP of cluster 3 was higher than those of clusters 1 and 2. CONCLUSIONS: Radiographs of TKA recipients with RA are increasingly presenting osteoarthritic features in recent decades. Key Points • Using automated measurement software, morphological parameters were measured from radiographs of 831 patients with rheumatoid arthritis who had undergone TKA in the past 16 years. • Cluster analysis based on the radiographic parameters revealed that the radiographs of patients with end-stage knee arthritis requiring total knee arthroplasty were classified into three groups. • In patients with rheumatoid arthritis who have undergone total knee arthroplasty in the past 16 years, the proportion of clusters with features of osteoarthritis and difficult-to-treat rheumatoid arthritis has increased, while the proportion of conventional rheumatoid arthritis has decreased.

Associated correction of forefoot alignment with hindfoot fusion for pes planovalgus deformity.

BACKGROUND: The present study aimed to investigate changes in hallux alignment after corrective surgery for adult-acquired flatfoot deformity (AAFD). PATIENTS AND METHODS: The present study retrospectively investigated the changes of hallux alignment in 37 feet (33 patients) which were treated with double or triple arthrodesis of the hindfoot for AAFD between 2015 and 2021 and could be followed up to one year postoperatively. RESULTS: Hallux valgus (HV) angle significantly decreased by a mean 4.1° among the whole 37 subjects and by a mean 6.6° among the 24 subjects who had a preoperative HV angle of 15° or more. Those who had HV correction (HV angle correction ≥ 5°) demonstrated more near-normal postoperative alignment of the medial longitudinal arch and hindfoot than those without HV correction. CONCLUSIONS: Hindfoot fusion for AAFD could improve preoperative HV deformity to some degree. HV correction was associated with proper realignment of the midfoot and hindfoot. LEVEL OF EVIDENCE: Level IV; retrospective case series.

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.

Interspecies Single-Cell RNA-Seq Analysis Reveals the Novel Trajectory of Osteoclast Differentiation and Therapeutic Targets.

Bone turnover is finely tuned by cells in the bone milieu, including osteoblasts, osteoclasts, and osteocytes. Osteoclasts are multinucleated giant cells with a bone-resorbing function that play a critical role in regulating skeletal homeostasis. Osteoclast differentiation is characterized by dramatic changes in morphology and gene expression following receptor activator of nuclear factor-kappa-Β ligand (RANKL) stimulation. We performed single-cell RNA-sequencing analyses of human and murine osteoclast-lineage cells (OLCs) and found that OLCs in the mitotic phase do not differentiate into mature osteoclasts. We also identified a guanosine triphosphatase (GTPase) family member, RAB38, as a highly expressed molecule in both human and murine osteoclast clusters; RAB38 gene expression is associated with dynamic changes in histone modification and transcriptional regulation. Silencing Rab38 expression by using short hairpin RNA (shRNA) inhibited osteoclast differentiation and maturation. In summary, we established an integrated fate map of human and murine osteoclastogenesis; this will help identify therapeutic targets in bone diseases. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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.

Transcription Factor Hematopoietically Expressed Homeobox Protein (Hhex) Negatively Regulates Osteoclast Differentiation by Controlling Cyclin-Dependent Kinase Inhibitors.

We investigated the role of hematopoietically expressed homeobox protein (Hhex) in osteoclast development. Trimethylation of lysine 27 of histone H3 at the cis-regulatory element of Hhex was maintained and that of lysine 4 was reduced during receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis, which was associated with a reduction of Hhex expression. Overexpression of Hhex in bone marrow-derived macrophages inhibited, whereas Hhex suppression promoted, RANKL-induced osteoclastogenesis in vitro. Conditional deletion of Hhex in osteoclast-lineage cells promoted osteoclastogenesis and reduced cancellous bone volume in mice, confirming the negative regulatory role of Hhex in osteoclast differentiation. Expression of cyclin-dependent kinase inhibitors such as Cdkn2a and Cdkn1b in osteoclast precursors was negatively regulated by Hhex, and Hhex deletion increased the ratio of cells at the G1 phase of the cell cycle. In conclusion, Hhex is an inhibitor of osteoclast differentiation that is regulated in an epigenetic manner and regulates the cell cycle of osteoclast precursors and the skeletal homeostasis. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Btn2a2 Regulates ILC2-T Cell Cross Talk in Type 2 Immune Responses.

Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. In vitro and in vivo experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. In vivo transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2-T cell interactions.

Inflammatory Arthritis and Bone Metabolism Regulated by Type 2 Innate and Adaptive Immunity.

While type 2 immunity has traditionally been associated with the control of parasitic infections and allergic reactions, increasing evidence suggests that type 2 immunity exerts regulatory functions on inflammatory diseases such as arthritis, and also on bone homeostasis. This review summarizes the current evidence of the regulatory role of type 2 immunity in arthritis and bone. Key type 2 cytokines, like interleukin (IL)-4 and IL-13, but also others such as IL-5, IL-9, IL-25, and IL-33, exert regulatory properties on arthritis, dampening inflammation and inducing resolution of joint swelling. Furthermore, these cytokines share anti-osteoclastogenic properties and thereby reduce bone resorption and protect bone. Cellular effectors of this action are both T cells (i.e., Th2 and Th9 cells), but also non-T cells, like type 2 innate lymphoid cells (ILC2). Key regulatory actions mediated by type 2 cytokines and immune cells on both inflammation as well as bone homeostasis are discussed.

Regulation of osteoarthritis development by ADAM17/Tace in articular cartilage.

INTRODUCTION: A disintegrin and metalloproteinase 17 (Adam17), also known as TNFα-converting enzyme (Tace), is a membrane-anchored protein involved in shedding of TNF, IL-6 receptor, ligands of epidermal growth factor receptor (EGFR), and Notch receptor. This study aimed to examine the role of Adam17 in adult articular cartilage and osteoarthritis (OA) pathophysiology. MATERIALS AND METHODS: Adam17 expression was examined in mouse knee joints during OA development. We analyzed OA development in tamoxifen-inducible chondrocyte-specific Adam17 knockout mice of a resection of the medial meniscus and medial collateral ligament (medial) model, destabilization of the medial meniscus (DMM) model, and aging model. We analyzed downstream pathways by in vitro experiments, and further performed intra-articular administration of an Adam17 inhibitor TAPI-0 for surgically induced mouse OA. RESULTS: Adam17 expression in mouse articular cartilage was increased by OA progression. In all models, Adam17 knockout mice showed ameliorated progression of articular cartilage degradation. Adam17 knockout decreased matrix metallopeptidase 13 (Mmp13) expression in both in vivo and in vitro experiments, whereas Adam17 activation by phorbol-12-myristate-13-acetate (PMA) increased Mmp13 and decreased aggrecan in mouse primary chondrocytes. Adam17 activation enhanced release of soluble TNF and transforming growth factor alpha, a representative EGF ligand, from mouse primary chondrocytes, while it did not change release of soluble IL-6 receptor or nuclear translocation of Notch1 intercellular domain. Intra-articular administration of the Adam17 inhibitor ameliorated OA progression. CONCLUSIONS: This study demonstrates regulation of OA development by Adam17, involvement of EGFR and TNF pathways, and the possibility of Adam17 as a therapeutic target for OA.

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.

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).

Evaluations of daily teriparatide using finite-element analysis over 12 months in rheumatoid arthritis patients.

INTRODUCTION: The objective of this study was to quantitatively evaluate the effects of daily teriparatide on rheumatoid arthritis patients using predicted bone strength (PBS) assessed by quantitative computed tomography-based finite-element analysis (QCT/FEA) and using bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA), and to prospectively investigate clinical determinants associated with PBS and BMD increases. MATERIALS AND METHODS: Participants comprised 39 patients (mean age, 69 years; disease activity score assessing 28 joints with CRP, 3.0; previous vertebral fractures, 82%) enrolled in this study. BMD by DXA and PBS by QCT/FEA of lumbar spine (LS) and proximal femur were measured at baseline, and after 6 and 12 months. In the groups showing increases in these values, variables that may have affected these increases were evaluated using univariate logistic regression analysis. RESULTS: Daily teriparatide treatment significantly increased not only LS BMD, but also LS PBS in RA patients with osteoporosis after both 6 and 12 months of treatment. Increases in N-terminal type I procollagen propeptide (PINP) at 1 and 3 months were significantly associated with increased LS PBS at 12 months according to univariate logistic regression analysis. The threshold value for increased PINP at 1 month for increased PBS at 12 months was 75 µg/L. CONCLUSIONS: Increased LS PBS at 12 months was predicted by increased PINP at 1 month from baseline.