Post-translational control of T cell development by the ESCRT protein CHMP5.

The acquisition of a protective vertebrate immune system hinges on the efficient generation of a diverse but self-tolerant repertoire of T cells by the thymus through mechanisms that remain incompletely resolved. Here we identified the endosomal-sorting-complex-required-for-transport (ESCRT) protein CHMP5, known to be required for the formation of multivesicular bodies, as a key sensor of thresholds for signaling via the T cell antigen receptor (TCR) that was essential for T cell development. CHMP5 enabled positive selection by promoting post-selection thymocyte survival in part through stabilization of the pro-survival protein Bcl-2. Accordingly, loss of CHMP5 in thymocyte precursor cells abolished T cell development, a phenotype that was 'rescued' by genetic deletion of the pro-apoptotic protein Bim or transgenic expression of Bcl-2. Mechanistically, positive selection resulted in the stabilization of CHMP5 by inducing its interaction with the deubiquitinase USP8. Our results thus identify CHMP5 as an essential component of the post-translational machinery required for T cell development.

Schnurri-3 inhibition suppresses bone and joint damage in models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to systemic and articular bone loss by activating bone resorption and suppressing bone formation. Despite current therapeutic agents, inflammation-induced bone loss in RA continues to be a significant clinical problem due to joint deformity and lack of articular and systemic bone repair. Here, we identify the suppressor of bone formation, Schnurri-3 (SHN3), as a potential target to prevent bone loss in RA. SHN3 expression in osteoblast-lineage cells is induced by proinflammatory cytokines. Germline deletion or conditional deletion of Shn3 in osteoblasts limits articular bone erosion and systemic bone loss in mouse models of RA. Similarly, silencing of SHN3 expression in these RA models using systemic delivery of a bone-targeting recombinant adenoassociated virus protects against inflammation-induced bone loss. In osteoblasts, TNF activates SHN3 via ERK MAPK-mediated phosphorylation and, in turn, phosphorylated SHN3 inhibits WNT/ß-catenin signaling and up-regulates RANKL expression. Accordingly, knock-in of a mutation in Shn3 that fails to bind ERK MAPK promotes bone formation in mice overexpressing human TNF due to augmented WNT/ß-catenin signaling. Remarkably, Shn3-deficient osteoblasts are not only resistant to TNF-induced suppression of osteogenesis, but also down-regulate osteoclast development. Collectively, these findings demonstrate SHN3 inhibition as a promising approach to limit bone loss and promote bone repair in RA.

WNT-modulating gene silencers as a gene therapy for osteoporosis, bone fracture, and critical-sized bone defects.

Treating osteoporosis and associated bone fractures remains challenging for drug development in part due to potential off-target side effects and the requirement for long-term treatment. Here, we identify recombinant adeno-associated virus (rAAV)-mediated gene therapy as a complementary approach to existing osteoporosis therapies, offering long-lasting targeting of multiple targets and/or previously undruggable intracellular non-enzymatic targets. Treatment with a bone-targeted rAAV carrying artificial microRNAs (miRNAs) silenced the expression of WNT antagonists, schnurri-3 (SHN3), and sclerostin (SOST), and enhanced WNT/ß-catenin signaling, osteoblast function, and bone formation. A single systemic administration of rAAVs effectively reversed bone loss in both postmenopausal and senile osteoporosis. Moreover, the healing of bone fracture and critical-sized bone defects was also markedly improved by systemic injection or transplantation of AAV-bound allograft bone to the osteotomy sites. Collectively, our data demonstrate the clinical potential of bone-specific gene silencers to treat skeletal disorders of low bone mass and impaired fracture repair.

Percutaneous distal chevron osteotomy is associated with lower immediate postoperative pain and a greater range of motion than the open technique: A prospective randomized study.

PURPOSE: The results of past studies comparing percutaneous techniques with traditional open techniques for hallux valgus are controversial. Therefore, this study aimed to compare the radiologic and clinical outcomes of percutaneous and open distal chevron osteotomies. METHODS: Seventy-one patients with mild to severe hallux valgus deformity were randomized to undergo percutaneous distal chevron osteotomy (percutaneous group, n = 36) or open distal chevron osteotomy (open group, n = 35) between October 2019 and September 2020. Radiological and clinical outcomes were assessed preoperatively and postoperatively. Outcome measures included the foot and ankle outcome score, foot functional index, visual analogue scale (VAS) scores for pain, range of motion (ROM) of the first metatarsophalangeal (MTP) joint, hallux valgus angle, intermetatarsal angle, and first metatarsal shortening. Additionally, the first metatarsal declination angle was measured to evaluate sagittal malunion. RESULTS: The mean first metatarsal declination angle decreased significantly at 12 months postoperatively in both groups (p = 0.021 and p < 0.001 in the percutaneous and open groups, respectively), and the decrement was significantly greater in the open group (p = 0.033). The mean VAS score for pain on postoperative day one was 4.2 ± 1.9 and 5.3 ± 1.7 in the percutaneous and open groups, respectively (p = 0.019). The mean ROM of the first MTP joint did not change significantly after surgery, from 72.5 ± 7.5 preoperatively to 71.0 ± 9.5 at 12 months postoperatively in the percutaneous group (p = 0.215); however, it decreased significantly from 70.6 ± 7.3 preoperatively to 63.4 ± 10.4 at 12 months postoperatively in the open group (p < 0.001). There were no significant differences between the groups regarding other clinical outcomes. CONCLUSION: The percutaneous group showed a lower immediate pain level at postoperative day 1 and better ROM of the first MTP joint at 12 months postoperatively.

Downregulation of the RNA-binding protein PUM2 facilitates MSC-driven bone regeneration and prevents OVX-induced bone loss.

BACKGROUND: Although mRNA dysregulation can induce changes in mesenchymal stem cell (MSC) homeostasis, the mechanisms by which post-transcriptional regulation influences MSC differentiation potential remain understudied. PUMILIO2 (PUM2) represses translation by binding target mRNAs in a sequence-specific manner. METHODS: In vitro osteogenic differentiation assays were conducted using human bone marrow-derived MSCs. Alkaline phosphatase and alizarin red S staining were used to evaluate the osteogenic potential of MSCs. A rat xenograft model featuring a calvarial defect to examine effects of MSC-driven bone regeneration. RNA-immunoprecipitation (RNA-IP) assay was used to determine the interaction between PUM2 protein and Distal-Less Homeobox 5 (DLX5) mRNA. Ovariectomized (OVX) mice were employed to evaluate the effect of gene therapy for postmenopausal osteoporosis. RESULTS: Here, we elucidated the molecular mechanism of PUM2 in MSC osteogenesis and evaluated the applicability of PUM2 knockdown (KD) as a potential cell-based or gene therapy. PUM2 level was downregulated during MSC osteogenic differentiation, and PUM2 KD enhanced MSC osteogenic potential. Following PUM2 KD, MSCs were transplanted onto calvarial defects in 12-week-old rats; after 8 weeks, transplanted MSCs promoted bone regeneration. PUM2 KD upregulated the expression of DLX5 mRNA and protein and the reporter activity of its 3'-untranslated region. RNA-IP revealed direct binding of PUM2 to DLX5 mRNA. We then evaluated the potential of adeno-associated virus serotype 9 (AAV9)-siPum2 as a gene therapy for osteoporosis in OVX mice. CONCLUSION: Our findings suggest a novel role for PUM2 in MSC osteogenesis and highlight the potential of PUM2 KD-MSCs in bone regeneration. Additionally, we showed that AAV9-siPum2 is a potential gene therapy for osteoporosis.

Deubiquitinating Enzyme USP7 Is Required for Self-Renewal and Multipotency of Human Bone Marrow-Derived Mesenchymal Stromal Cells.

Ubiquitin-specific protease 7 (USP7) is highly expressed in a variety of malignant tumors. However, the role of USP7 in regulating self-renewal and differentiation of human bone marrow derived mesenchymal stromal cells (hBMSCs) remains unknown. Herein, we report that USP7 regulates self-renewal of hBMSCs and is required during the early stages of osteogenic, adipogenic, and chondrogenic differentiation of hBMSCs. USP7, a deubiquitinating enzyme (DUB), was found to be downregulated during hBMSC differentiation. Furthermore, USP7 is an upstream regulator of the self-renewal regulating proteins SOX2 and NANOG in hBMSCs. Moreover, we observed that SOX2 and NANOG are poly-ubiquitinated and their expression is downregulated in USP7-deficient hBMSCs. Overall, this study showed that USP7 is required for maintaining self-renewal and multipotency in cultured hBMSCs. Targeting USP7 might be a novel strategy to preserve the self-renewal capacity of hBMSCs intended for stem cell therapy.

Outcomes of oblique supramalleolar osteotomy without fibular osteotomy for congruent- and incongruent-type medial ankle arthritis.

BACKGROUND: Although high talar tilt and ankle mortise incongruence are risk factors for supramalleolar osteotomy (SMO), no study on lateral talofibular joint congruence exists. We aimed to evaluate the outcomes of oblique SMO without fibular osteotomy for medial ankle arthritis and compare them according to the lateral talofibular joint congruity. METHODS: Forty-eight ankles were retrospectively reviewed and divided according to preoperative talofibular joint congruity (congruent, 22 [45.8%] vs. incongruent, 26 [54.2%]). RESULTS: The mean VAS score, AOFAS score, and modified Takakura stage were significantly improved. No significant differences were noted in clinical outcomes, but the mean postoperative tibiotalar angle and difference between the upper and lower talofibular gaps were significantly different in both groups (p = 0.004 and p = 0.009, respectively). The mean Takakura stage at 1 and 2 years after surgery was higher in the incongruent group (p = 0.013, p = 0.012). CONCLUSION: This procedure was effective against early- to mid-stage medial ankle arthritis. Radiographic arthritic grade changed according to the talofibular joint congruity.

Cellular and Tissue Selectivity of AAV Serotypes for Gene Delivery to Chondrocytes and Cartilage.

Background: Despite several studies on the effect of adeno-associated virus (AAV)-based therapeutics on osteoarthritis (OA), information on the transduction efficiency and applicable profiles of different AAV serotypes to chondrocytes in hard cartilage tissue is still limited. Moreover, the recent discovery of additional AAV serotypes makes it necessary to screen for more suitable AAV serotypes for specific tissues. Here, we compared the transduction efficiencies of 14 conventional AAV serotypes in human chondrocytes, mouse OA models, and human cartilage explants obtained from OA patients. Methods: To compare the transduction efficiency of individual AAV serotypes, green fluorescent protein (GFP) expression was detected by fluorescence microscopy or western blotting. Likewise, to compare the transduction efficiencies of individual AAV serotypes in cartilage tissues, GFP expression was determined using fluorescence microscopy or immunohistochemistry, and GFP-positive cells were counted. Results: Only AAV2, 5, 6, and 6.2 exhibited substantial transduction efficiencies in both normal and OA chondrocytes. All AAV serotypes except AAV6 and rh43 could effectively transduce human bone marrow mesenchymal stem cells. In human and mouse OA cartilage tissues, AAV2, AAV5, AAV6.2, AAV8, and AAV rh39 showed excellent tissue specificity based on transduction efficiency. These results indicate the differences in transduction efficiencies of AAV serotypes between cellular and tissue models. Conclusions: Our findings indicate that AAV2 and AAV6.2 may be the best choices for AAV-mediated gene delivery into intra-articular cartilage tissue. These AAV vectors hold the potential to be of use in clinical applications to prevent OA progression if appropriate therapeutic genes are inserted into the vector.

Primary Autologous Osteochondral Transfer Shows Superior Long-Term Outcome and Survival Rate Compared With Bone Marrow Stimulation for Large Cystic Osteochondral Lesion of Talus.

PURPOSE: To compare the results of bone marrow stimulation (BMS) versus autologous osteochondral transfer (AOT) as primary surgical option for large cystic osteochondral lesion of talus (OLT) and to further distinguish factors associated with clinical failures and overall survival. METHODS: We retrospectively analyzed patients with symptomatic large cystic OLT (>300 mm3) who underwent either primary BMS or AOT between January 2001 and January 2016 with a minimum follow-up of 36 months. Lesion surface area and volume were measured on magnetic resonance imaging. Clinical outcomes were assessed using pain visual analog scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS) score, and Foot and Ankle Outcome Score (FAOS). Survival outcomes and factors associated with clinical failures were evaluated using Kaplan-Meier analysis and Cox regression analyses, respectively. RESULTS: Fifty of the total 853 patients had large cystic OLTs. Thirty-two patients underwent primary BMS, and 18 patients underwent primary AOT. Mean follow-up period was 118 months, and average lesion surface area and volume were 152.8 mm2 and 850.7 mm3, respectively. The primary AOT group showed significantly superior improvements in clinical outcomes compared with the BMS group at last follow-up (P = .001). Fourteen patients in the primary BMS group and 2 patients in the primary AOT group experienced clinical failure. Kaplan-Meier analysis showed a superior survival rate of primary AOT (P = .042). Syndesmosis widening (hazard ratio 12.361; P = .004) and large lesion surface area (hazard ratio 1.011; P = .014) were significant relative risks of clinical failure in the primary BMS group. However, lesion volume showed no significant relationship with clinical failure. CONCLUSION: Long-term results of primary AOT showed superior clinical improvements and survival rate in treating large cystic OLT. Risk factors for failure in the primary BMS group were large lesion surface area and syndesmosis widening. STUDY DESIGN: Retrospective comparative study LEVEL OF EVIDENCE: III.

Therapeutic Potential of Tauroursodeoxycholic Acid for the Treatment of Osteoporosis.

Tauroursodeoxycholic acid (TUDCA) is a US FDA-approved hydrophilic bile acid for the treatment of chronic cholestatic liver disease. In the present study, we investigate the effects of TUDCA on the proliferation and differentiation of osteoblasts and its therapeutic effect on a mice model of osteoporosis. Following treatment with different concentrations of TUDCA, cell viability, differentiation, and mineralization were measured. Three-month-old female C57BL/6 mice were randomly divided into three groups (n = 8 mice per group): (i) normal mice as the control group, (ii) ovariectomy (OVX) group (receiving phosphate-buffered saline (PBS) treatment every other day for 4 weeks), and (iii) OVX group with TUDCA (receiving TUDCA treatment every other day for 4 weeks starting 6 weeks after OVX). At 11 weeks post-surgery, serum levels of procollagen type I N-terminal propeptides (PINP) and type I collagen crosslinked C-telopeptides (CTX) were measured, and all mice were sacrificed to examine the distal femur by micro-computed tomography (CT) scans and histology. TUDCA (100 nM, 1 µM) significantly increased the proliferation and viability of osteoblasts and osteoblast differentiation and mineralization when used in vitro. Furthermore, TUDCA neutralized the detrimental effects of methylprednisolone (methylprednisolone-induced osteoblast apoptosis). In the TUDCA treatment group the PINP level was higher and the CTX level was lower, but these levels were not significantly different compared to the PBS treatment group. Micro-CT and histology showed that the TUDCA treatment group preserved more trabecular structures in the distal femur compared to the PBS treatment group. In addition, the TUDCA treatment group increased the percentage bone volume with respect to the total bone volume, bone mineral density, and mice distal femur trabeculae compared with the PBS treatment group. Taken together, our findings suggest that TUDCA may provide a favorable effect on bones and could be used for the prevention and treatment of osteoporosis.

The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis.

Mitogen-activated protein kinases (MAPKs) are a family of protein kinases that function as key signal transducers of a wide spectrum of extracellular stimuli, including growth factors and pro-inflammatory cytokines. Dysregulation of the extracellular signal-regulated kinase (ERK) MAPK pathway is associated with human skeletal abnormalities including Noonan syndrome, neurofibromatosis type 1, and cardiofaciocutaneous syndrome. Here, we demonstrate that ERK activation in osteoprogenitors is required for bone formation during skeletal development and homeostasis. Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1OsxMek2-/-), resulted in severe osteopenia and cleidocranial dysplasia (CCD), similar to that seen in humans and mice with impaired RUNX2 function. Additionally, tamoxifen-induced deletion of Mek1 and Mek2 in osteoprogenitors in adult mice (Mek1Osx-ERTMek2-/-) significantly reduced bone mass. Mechanistically, this corresponded to decreased activation of osteoblast master regulators, including RUNX2, ATF4, and ß-catenin. Finally, we identified potential regulators of osteoblast differentiation in the ERK MAPK pathway using unbiased phospho-mass spectrometry. These observations demonstrate essential roles of ERK activation in osteogenesis and bone formation.

p38α MAPK is required for tooth morphogenesis and enamel secretion.

An improved understanding of the molecular pathways that drive tooth morphogenesis and enamel secretion is needed to generate teeth from organ cultures for therapeutic implantation or to determine the pathogenesis of primary disorders of dentition (Abdollah, S., Macias-Silva, M., Tsukazaki, T., Hayashi, H., Attisano, L., and Wrana, J. L. (1997) J. Biol. Chem. 272, 27678-27685). Here we present a novel ectodermal dysplasia phenotype associated with conditional deletion of p38α MAPK in ectodermal appendages using K14-cre mice (p38α(K14) mice). These mice display impaired patterning of dental cusps and a profound defect in the production and biomechanical strength of dental enamel because of defects in ameloblast differentiation and activity. In the absence of p38α, expression of amelogenin and ß4-integrin in ameloblasts and p21 in the enamel knot was significantly reduced. Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects, implying that MKK6 functions as an upstream kinase of p38α in ectodermal appendages. Lastly, stimulation with BMP2/7 in both explant culture and an ameloblast cell line confirm that p38α functions downstream of BMPs in this context. Thus, BMP-induced activation of the p38α MAPK pathway is critical for the morphogenesis of tooth cusps and the secretion of dental enamel.

Different effects of resveratrol on early and late passage mesenchymal stem cells through ß-catenin regulation.

Resveratrol is a sirtuin 1 (SIRT1) activator and can function as an anti-inflammatory and antioxidant factor. In mesenchymal stem cells (MSCs), resveratrol enhances the proliferation and differentiation potential and has an anti-aging effect. However, contradictory effects of resveratrol on MSC cultures have been reported. In this study, we found that resveratrol had different effects on MSC cultures according to their cell passage and SIRT1 expression. Resveratrol enhanced the self-renewal potential and multipotency of early passage MSCs, but accelerated cellular senescence of late passage MSCs. In early passage MSCs expressing SIRT1, resveratrol decreased ERK and GSK-3ß phosphorylation, suppressing ß-catenin activity. In contrast, in late passage MSCs, which did not express SIRT1, resveratrol increased ERK and GSK-3ß phosphorylation, activating ß-catenin. We confirmed that SIRT1-deficient early passage MSCs treated with resveratrol lost their self-renewal potential and multipotency, and became senescent due to increased ß-catenin activity. Sustained treatment with resveratrol at early passages maintained the self-renewal potential and multipotency of MSCs up to passage 10. Our findings suggest that resveratrol can be effectively applied to early passage MSC cultures, whereas parameters such as cell passage and SIRT1 expression must be taken into consideration before applying resveratrol to late passage MSCs.

Interleukin-6 induces the lineage commitment of bone marrow-derived mesenchymal multipotent cells through down-regulation of Sox2 by osteogenic transcription factors.

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are a heterogeneous population of cells that differ in size and morphology. BM-MSCs become committed to the osteogenic lineage as senescence approaches and lose multipotency. Nevertheless, little is known about the effects of cell-cell interaction between different populations on stemness loss and lineage commitment. The current study aimed to identify mechanisms by which cell-cell interactions between heterogeneous BM-MSCs affect stemness and lineage commitment of multipotent subpopulation. The lineage commitment of primitive multipotent cells was strongly induced in the presence of cytokines secreted by senescent-like cells in a cell culture insert system. Senescent-like cells secreted higher levels of interleukin-6 (IL-6) than primitive multipotent cells in a human cytokine array. IL-6 induced the lineage commitment and stemness loss in multipotent cells by decreasing Sox2 expression. Furthermore, we confirmed that IL-6 decreased the transcriptional activity of Sox2 through up-regulation of Runx2 and Dlx5. We suggest a mechanism by which IL-6 modulates the expression of Sox2, resulting in decreased multipotency and causing primitive multipotent cells to undergo osteogenic lineage commitment. This is the first study to identify mechanisms in which the cell-cell interactions between the different populations play important roles in the stemness loss and lineage commitment of multipotent populations.-Yoon, D. S., Kim, Y. H., Lee, S., Lee, K.-M., Park, K. H., Jang, Y., Lee, J. W. Interleukin-6 induces the lineage commitment of bone marrow-derived mesenchymal multipotent cells through down-regulation of Sox2 by osteogenic transcription factors.

Age-Related Decrease in Pellino-1 Expression Contributes to Osteoclast-Mediated Bone Loss.

Aging-related bone loss is driven by various biological factors, such as imbalanced bone metabolism from decreased osteoblast and increased osteoclast activities. Various transcriptional and post-transcriptional factors increase osteoclast activity with aging; however, studies regarding the post-translational regulators of osteoclast activity are still limited. The ubiquitin E3 ligase Pellino-1 is a well-known post-translational regulator of inflammation. However, how Pellino-1 expression regulation affects osteoclast differentiation remains unclear. This study determined that Pellino-1 levels are reduced in bone marrow monocytes (BMMs) from 40-week-old mice compared to 4-week-old mice. Interestingly, conditional Knockout (cKO) of Pellino-1 in 6-week-old mice resulted in decreased bone mass, reduced body size, and lower weight than in Pellino-1 floxed mice; however, these differences are not observed in 20-week-old mice. The increased number of tartrate-resistant acid phosphatase (TRAP)-positive cells and serum levels of C-terminal telopeptides of type I collagen, a marker of bone resorption, in 6-week-old Pellino-1 cKO mice implied a connection between Pellino-1 and the osteoclast population. Enhanced TRAP activity and upregulation of osteoclast genes in BMMs from the cKO mice indicate that Pellino-1 deletion affects osteoclast differentiation, leading to decreased bone mass and heightened osteoclast activity. Thus, targeting Pellino-1 could be a potential gene therapy for managing and preventing osteoporosis.

Zinc inhibits osteoclast differentiation by suppression of Ca2+-Calcineurin-NFATc1 signaling pathway.

BACKGROUND: Zinc, an essential trace element, inhibits osteoclast differentiation in vitro and in vivo. The molecular mechanism for the inhibitory effect of zinc, however, is poorly understood. The purpose of this study was to investigate the effect of zinc and determine its molecular mechanism on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis in mouse bone marrow-derived monocyte cells (BMMs) and RAW264.7 cells. RESULTS: In BMMs, zinc treatment during osteoclast differentiation decreased RANKL-induced osteoclast formation in a dose-dependent manner. We show that zinc suppressed the mRNA levels of nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1). Zinc also accumulated phospho-Nfatc1 (p-Nfatc1) in the cytosol in a dose-dependent manner and inhibited the translocation of Nfatc1 to the nucleus in RAW264.7 cells. Zinc suppressed the activities of Nfatc1 in the nucleus without changing the activities of NF-κB in RAW264.7 cells. In contrast, calcineurin activity decreased in response to zinc but its protein level was unchanged. RANKL-induced Ca2+ oscillations were inhibited by zinc treatment, but phospho-phospholipase Cγ1 (p-PLCγ1), the upstream signaling molecule of Ca2+ oscillations, was unaffected. Moreover, a constitutively active form of Nfatc1 obviously rescued suppression of osteoclastogenesis by zinc. CONCLUSIONS: Taken together, these results demonstrate for the first time that the inhibitory effect of zinc during osteoclastogesis is caused by suppressing the Ca2+-Calcineurin-NFATc1 signaling pathway. Thus, zinc may be a useful therapeutic candidate for the prevention of bone loss caused by NFATc1 activation in osteoclasts.

OK-432 sclerotherapy for malleolar bursitis of the ankle.

BACKGROUND: The purpose of this study was to evaluate the clinical outcomes and usefulness of OK-432 (Picibanil) sclerotherapy as a new option in the conservative treatment of patients with malleolar bursitis of the ankle. METHODS: Retrospectively, we reviewed a total of 20 consecutive patients (20 feet) in whom OK-432 sclerotherapy had been performed between March 2009 and June 2010. After aspiration of fluid in the malleolar bursal sac, 0.05 mg of OK-432 was injected into the malleolar bursal sac. We evaluated the clinical outcomes and side effects at the following time points: 2 weeks, 1 month, 3 months, 6 months, and 1 year after OK-432 sclerotherapy. The responses to the treatment were assessed according to the degree of fluctuation, shrinkage of the bursal sac, and soft tissue swelling. RESULTS: Complete resolution was observed in 19 patients (95%) after the first or second application of OK-432 sclerotherapy, and a partial response was observed in 1 patient (5%) after a second application of OK-432 sclerotherapy. The physical component scores of SF-36 improved from 70.0 ± 6.8 to 76.5 ± 7.3 at the last follow-up (P = .0002). CONCLUSION: OK-432 sclerotherapy was a useful procedure for patients not responding to the usual conservative treatment of malleolar bursitis of the ankle. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Medial Reduction in Sesamoid Position after Hallux Valgus Correction Surgery Showed Better Outcome in S.E.R.I. Osteotomy than DCMO.

BACKGROUND: The purpose of the present study was to compare the degree of sesamoid reduction after hallux valgus correction between distal chevron metatarsal osteotomy (DCMO) and S.E.R.I. (simple, effective, rapid, and inexpensive) osteotomy, and to analyze the effects on the recurrence of hallux valgus. METHODS: We retrospectively analyzed the foot radiographs of 60 feet (30 DCMO and 30 SERI) treated for hallux valgus from August 2013 to July 2017. Radiographic assessments were performed preoperatively, at early follow-up (at a mean of 3.1 months) and at the most recent follow-up (at a mean of 16.7 months). The location of the medial sesamoid was classified into seven stages, in accordance with the method described by Hardy and Clapham; stage IV or less was defined as the normal position for the medial sesamoid, and stage V or greater was defined as lateral displacement of the sesamoid. The pre- and post-operative hallux valgus angle, 1-2 intermetatarsal angle, and sesamoid position were compared between the two groups. RESULTS: The mean follow-up period was 18.4 (12-36) months in the DCMO group and 15.0 (12-36) months in the S.E.R.I. group (p = 0.108). The radiologic results showed that the hallux valgus angles were not significantly different between the two groups preoperatively and at the early follow-up: preoperatively, they were 28.8 ± 7.7 in the DCMO group and 32.6 ± 9.5 in the S.E.R.I. group (p = 0.101), and they were 10.4 ± 4.0 and 8.7 ± 5.0 (p = 0.148) at the early follow-up, respectively. However, at the most recent follow-up, the DCMO group (13.9 ± 5.6) showed significantly higher hallux valgus angles than the S.E.R.I. group (10.4 ± 6.4, p = 0.030), and there were no differences between the recurrence of hallux valgus in the DCMO group (13%)and that in the S.E.R.I. group (10%) (p = 0.553). There were no significant differences in the 1-2 intermetatarsal angles between the two groups at the early follow-up (6.1 ± 2.5 vs. 4.8 ± 3.1, p = 0.082) and at the most recent follow-up (7.3 ± 2.9 vs. 6.6 ± 3.5, p = 0.408). After hallux-valgus-correction surgery, the stage change of the tibia sesamoid position from the preoperative stage to the initial follow-up was significantly larger in the S.E.R.I. group (-4.4 ± 1.4) than in the DCMO group (-3.4 ± 1.1) (p = 0.003); the changes from the preoperative stage to the last follow-up were also significantly larger in the SERI group (-3.3 ± 1.7) than in the DCMO group (-2.4 ± 1.5) (p = 0.028); however, the changes from the initial follow-up to the last follow-up showed no significant differences between the two groups (+1.0 ± 1.1 in the DCMO group vs. +1.1 ± 1.2 in the S.E.R.I. group) (p = 0.822). The medial sesamoid was laterally subluxated in all the preoperative cases in the DCMO and S.E.R.I. groups. The lateral subluxation of the tibia sesamoid was more frequently observed in the DCMO group (four cases, 13%) than in the S.E.R.I. group (0 cases, 0%) (p = 0.038) at the early follow-up. CONCLUSION: In conclusion, our results demonstrated that the S.E.R.I. procedure is superior to DCMO in decreasing the hallux valgus angle and showed that the early post-operative reduction in the sesamoids can be a risk factor for the recurrence of hallux valgus.

Minimally Invasive Transverse Distal Metatarsal Osteotomy (MITO) for Hallux Valgus Correction: Early Outcomes of Mild to Moderate vs Severe Deformities.

BACKGROUND: We compared the radiological and clinical outcomes of mild to moderate and severe hallux valgus (HV) treated with minimally invasive distal metatarsal transverse osteotomy (MITO) performed by a single surgeon. METHODS: Eighty-four patients who underwent MITO between May 2018 and March 2020 were recruited and followed for at least 24 months. The severe group was defined as having a preoperative hallux valgus angle (HVA) >40 degrees or preoperative first-to-second intermetatarsal angle (1-2 IMA) >16 degrees; the mild to moderate group was defined as having an HVA <40 degrees and a 1-2 IMA <16 degrees. Pre- and postoperative measurements of the HVA, 1-2 IMA, distal metatarsal articular angle, and tibial sesamoid position were obtained. The visual analog scale for pain, the Foot and Ankle Outcome Score, and the Medical Outcomes Study Short Form Health Survey-36 physical component summary were used to assess clinical outcomes. RESULTS: A total of 116 feet were included in this study and median follow-up period of 29.0 months (range, 24-52 months). Both groups showed significant improvements in all radiologic parameters postoperatively, with the degrees of correction greater in the severe group than in the mild to moderate group. All clinical scores improved significantly from the preoperative to the last follow-up visit. Final clinical outcomes and degrees of improvement were comparable in both groups. CONCLUSION: This study showed that short-term radiographic results for patients with either mild to moderate or severe HV treated with MITO were favorable. Overall clinical outcomes were comparable to those of conventional treatments. In this series, we found MITO with screw fixation to be a satisfactory surgical option for patients with mild to severe HV deformities. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Inhibiting the cytosolic function of CXXC5 accelerates diabetic wound healing by enhancing angiogenesis and skin repair.

Diabetic wound healing, including diabetic foot ulcer (DFU), is a serious complication of diabetes. Considering the complexity of DFU development, the identification of a factor that mediates multiple pathogeneses is important for treatment. In this study, we found that CXXC-type zinc finger protein 5 (CXXC5), a negative regulator of the Wnt/ß-catenin pathway, was overexpressed with suppression of the Wnt/ß-catenin pathway and its target genes involved in wound healing and angiogenesis in the wound tissues of DFU patients and diabetes-induced model mice. KY19334, a small molecule that activates the Wnt/ß-catenin pathway by inhibiting the CXXC5-Dvl interaction, accelerated wound healing in diabetic mice. The enhancement of diabetic wound healing could be achieved by restoring the suppressed Wnt/ß-catenin signaling and subsequently inducing its target genes. Moreover, KY19334 induced angiogenesis in hindlimb ischemia model mice. Overall, these findings revealed that restorative activation of Wnt/ß-catenin signaling by inhibiting the function of cytosolic CXXC5 could be a therapeutic approach for treating DFUs.