Exploration of the miR-187-3p/CNR2 pathway in modulating osteoblast differentiation and treating postmenopausal osteoporosis through mechanical stress.

This study aimed to explore how mechanical stress affects osteogenic differentiation via the miR-187-3p/CNR2 pathway. To conduct this study, 24 female C57BL/6 mice, aged 8 weeks, were used and divided into four groups. The Sham and OVX groups did not undergo treadmill exercise, while the Sham + EX and OVX + EX groups received a 8-week treadmill exercise. Post-training, bone marrow and fresh femur samples were collected for further analysis. Molecular biology analysis, histomorphology analysis, and micro-CT analysis were conducted on these samples. Moreover, primary osteoblasts were cultured under osteogenic conditions and divided into GM group and CTS group. The cells in the CTS group underwent a sinusoidal stretching regimen for either 3 or 7 days. The expression of early osteoblast markers (Runx2, OPN, and ALP) was measured to assess differentiation. The study findings revealed that mechanical stress has a regulatory impact on osteoblast differentiation. The expression of miR-187-3p was observed to decrease, facilitating osteogenic differentiation, while the expression of CNR2 increased significantly. These observations suggest that mechanical stress, miR-187-3p, and CNR2 play crucial roles in regulating osteogenic differentiation. Both in vivo and in vitro experiments have confirmed that mechanical stress downregulates miR-187-3p and upregulates CNR2, which leads to the restoration of distal femoral bone mass and enhancement of osteoblast differentiation. Therefore, mechanical stress promotes osteoblasts, resulting in improved osteoporosis through the miR-187-3p/CNR2 signaling pathway. These findings have broad prospect and provide molecular biology guidance for the basic research and clinical application of exercise in the prevention and treatment of PMOP.

Hierarchically Assembled Nanofiber Scaffold Guides Long Bone Regeneration by Promoting Osteogenic/Chondrogenic Differentiation of Endogenous Mesenchymal Stem Cells.

Critical-sized segmental long bone defects represent a challenging clinical dilemma in the management of battlefield and trauma-related injuries. The residual bone marrow cavity of damaged long bones contains many bone marrow mesenchymal stem cells (BMSCs), which provide a substantial source of cells for bone repair. Thus, a three-dimensional (3D) vertically aligned nanofiber scaffold (VAS) is developed with long channels and large pore size. The pore of VAS toward the bone marrow cavity after transplantation, enables the scaffolds to recruit BMSCs from the bone marrow cavity to the defect area. In vivo, it is found that VAS can significantly shorten gap distance and promote new bone formation compared to the control and collagen groups after 4 and 8 weeks of implantation. The single-cell sequencing results discovered that the 3D nanotopography of VAS can promote BMSCs differentiation to chondrocytes and osteoblasts, and up-regulate related gene expression, resulting in enhancing the activities of bone regeneration, endochondral ossification, bone trabecula formation, bone mineralization, maturation, and remodeling. The Alcian blue and bone morphogenetic protein 2 (BMP-2) immunohistochemical staining verified significant cartilage formation and bone formation in the VAS group, corresponding to the single-cell sequencing results. The study can inspire the design of next-generation scaffolds for effective long-bone regeneration is expected by the authors.

Preoperative temporary fixation for fractures around the ankle using a simple extensible external fixator significantly improves patient comfort.

BACKGROUND: The authors developed a simple extensible external fixator, which has the advantages of easy application and inexpensiveness. The present study aimed to make a comparison between this external fixator and calcaneal traction in preoperative temporary fixation for malaligned ankle fractures and pilon fractures. METHODS: From May 2020 to February 2022, patients with malaligned ankle fractures or Rüedi-Allgöwer type 2 or 3 pilon fractures with obvious soft tissue swelling were retrospectively reviewed and divided into the calcaneal traction group and the external fixation group. The two groups of patients were matched 1:1 before making comparisons. RESULTS: A total of 38 patients were included. Higher General Comfort Questionnaire score and lower visual analog scale score were noticed in the external fixation group during hospitalization (p < 0.05), while the operation latency time, total cost, patient satisfaction, and functional outcomes one year after surgery were not significantly different between the two groups. No wound complications were observed. CONCLUSION: Preoperative temporary fixation for fractures around the ankle using this simple extensible external fixator significantly improves patient comfort when compared to calcaneal traction. LEVEL OF EVIDENCE: III, retrospective comparative study.

The lasso-loop technique is equivalent to the simple suture technique in arthroscopic anterior talofibular ligament repair.

PURPOSE: To compare the clinical outcomes of the lasso-loop and simple suture techniques in arthroscopic anterior talofibular ligament (ATFL) repair for the treatment of chronic lateral ankle instability (CLAI). METHODS: From 2018 to 2020, patients with CLAI who underwent arthroscopic ATFL repair using the lasso-loop or simple suture technique were matched 1:1 (arthroscopic lasso-loop [AL] group, n = 29; simple arthroscopic suture [AS] group, n = 29) based on age, sex, affected side, body mass index, and follow-up duration using propensity score matching and retrospectively evaluated. Karlsson score, visual analogue scale (VAS) score, Tegner score, anterior drawer test (ADT) results, complications, patient-reported satisfaction, and magnetic resonance (MR) re-evaluation findings of ATFL quality were used to describe the outcomes. RESULTS: The patient characteristics or follow-up durations did not significantly differ between the two groups. The Karlsson score, VAS score, and Tegner score improved significantly in both groups after a mean follow-up duration of 29.6 ± 2.8 months. The postoperative clinical scores, ADT results, satisfaction rates, complication rates and MR re-evaluation findings were not significantly different between the two groups at the latest follow-up. CONCLUSION: The lasso-loop technique was equivalent to the simple suture technique in arthroscopic ATFL repair for the treatment of CLAI after a minimum follow-up of 2 years, suggesting that the simple suture technique is sufficient for arthroscopic ATFL repair in most patients without the need to add a lasso loop. LEVEL OF EVIDENCE: Level III.

Effect of bone marrow mesenchymal stem cell transplantation combined with lugua polypeptide injection on osteoarthritis in rabbit knee joint.

PURPOSE: This study aimed to elucidate the effect of bone marrow mesenchymal stem cell (BMSC) transplantation combined with the administration of Lugua polypeptide injection into the knee joint cavity to treat knee osteoarthritis (KOA) in rabbits. MATERIAL AND METHODS: Sixty white New Zealand rabbits were randomly divided into the blank, model, Lugua polypeptide, BMSC, and combined (Lugua polypeptide plus BMSC) groups, with 12 rabbits in each group. The mRNA and protein expression levels of cyclin D1, bcl-2, TIMP-1, p21, caspase-3, Bax, MMP-1, MMP-13, TLR-4, and NF-κB p65 in chondrocytes, and levels of IL-1, NO, TNF-α, and IL-6 in the synovial fluid were compared. RESULTS: The severity of cartilage damage in the combined group was significantly less (P <0.01). Compared to the MG, the mRNA and protein expression levels of cyclin D1, bcl-2 and TIMP-1 in chondrocytes of the three other groups were significantly increased, while those of p21, caspase-3, Bax, MMP-1, MMP-13, TLR-4, and NF-κB p65 in the chondrocytes and levels of IL-1, NO, TNF-α, and IL-6 in the synovial fluid of the three other groups were significantly reduced (P <0.05). The aforementioned indicators in the combined group were significantly better than those of the Lugua polypeptide and BMSCs groups (P <0.05). CONCLUSIONS: BMSC transplantation combined with Lugua polypeptide injection may improve KOA-related cartilage tissue damage in rabbits.

Design, synthesis, and bioevaluation of imidazo [1,2-a] pyrazine derivatives as tubulin polymerization inhibitors with potent anticancer activities.

Through structural optimization and ring fusion strategy, we designed a series of novel imidazo[1,2-a]pyrazine derivatives as potential tubulin inhibitors. These compounds displayed potent anti-proliferative activities (micromolar to nanomolar) against a panel of cancer cell lines (including HepG-2, HCT-116, A549 and MDA-MB-231 cells). Among them, compound TB-25 exhibited the strongest inhibitory effects against HCT-116 cells with an IC50 of 23 nM. Mechanism studies revealed that TB-25 could effectively inhibit tubulin polymerization in vitro, and destroy the dynamic equilibrium of microtubules in HCT-116 cells. In addition, TB-25 dose-dependently induced G2/M phase cell cycle arrest and apoptosis in HCT-116 cells. Furthermore, TB-25 suppressed HCT-116 cell migration in a concentration-dependent manner. Finally, molecular docking showed that TB-25 fitted well in the colchicine binding site of tubulin and overlapped nicely with CA-4. Collectively, these results suggest that TB-25 represents a promising tubulin inhibitor deserving further investigation.

Identification and validation of MicroRNA-mRNA Networks in Dorsal Root Ganglia after Peripheral Nerve Injury.

Changes in DRG after nerve injury involve neuronal damage, apoptosis, pain transmission, and activation of regenerative programs. It is unclear which genes and microRNAs may play a major role in this process. Therefore, this study performed a meta-analysis of previously published gene expression data to reveal the potential microRNA-mRNA network in dorsal root ganglia (DRG) after peripheral nerve injury. We searched 5 mRNA and 3 microRNA expression data sets, obtained 447 differentially expressed genes (DEGs) and 5 differentially expressed miRNAs, determined the biological pathways enriched by these DEGs, and further predicted new microRNA-mRNA interactions, such as miR-21/Hmg20a, miR-221/Ube2ql1, miR-30c-1/Rhoq, miR-500/Sema3c, and miR-551b/Cdc42se2. We verified these hub mRNA and miRNA in rats by qRT-PCR and found the results were consistent with the bioinformatics analysis. And we predicted transcription factors associated with these genes (gTFs) and TFs associated with these microRNAs (mTFs) and constructed the mTF-miRNA-gene-gTF regulatory network to further explore the molecular mechanism in DRG. Finally, we compared the DRG transcriptome after PNI to that of chronic constriction injury (CCI), and found that PNI caused greater damage to DRG compared to CCI. At the same time, the related mechanisms of pain caused by the two pathophysiological process may be different.

Technique Tip: Correcting Malalignment of the Talus Using a Pin-Based Distracter During Arthroscopic Ankle Arthrodesis.

It is technical demanding work to perform arthroscopic ankle arthrodesis to treat end-stage ankle osteoarthritis with excessive talar tilt. This article aimed to provide an effective technique tip for the treatment of Takakura stage 3b ankle osteoarthritis with a talar tilt angle more than 15 degrees under arthroscopy. A conventional anterior arthroscopic approach is used. After arthroscopic examination and debridement, one pin which is parallel to the distal tibial surface is inserted into the tibial side of the ankle, the other pin which is parallel to the talar dome surface is inserted into the talar side of the ankle, both at the coronal plane. Then a distracter is used in the medial side to open the interspace of the tibiotalar joint and correct the talar tilt through the 2 pins, under which circumstance the tibiotalar joint surface can be well prepared. Next an anti-distracter is used in the lateral side to close the tibiotalar interspace and correct the talar tilt through the 2 pins, in which condition 3 fully threaded cannulated lag screws can be inserted through guide pins in a cross pattern to fix the ankle joint. We used the pin-based distracter to open and close tibiotalar interspace, correct the talar tilt and maintain a good mechanical axis for fusion, and the outcomes were good.

Topical Application of Tranexamic Acid Can Reduce Postoperative Blood Loss in Calcaneal Fractures: A Randomized Controlled Trial.

The traditional lateral "L" approach is common for managing calcaneal fractures with a drawback of significant blood loss. Yet there are no prospective studies on the hemostatic effect of the topical use of tranexamic acid (TXA) in calcaneal fracture surgeries. The purpose of this study was to evaluate the role of topical administration of TXA in reducing postoperative blood loss in calcaneal fractures. Forty participants were randomly distributed into the TXA group (n = 20) and the control group (n = 20). All participants underwent the same surgery via the lateral "L" approach. At the end of the operation, the surgical wound was irrigated with 80 mL 0.5 g/L TXA in the TXA group and 80 mL 0.9% sodium chloride in the control group, followed by the routine use of a drainage tube when closing the incision. Then, 20 mL 0.5 g/L TXA (TXA group) or 20 mL 0.9% sodium chloride solution (control group) was injected retrogradely into the wound through the drainage tube, which was clipped for 30 minutes thereafter. There were no significant differences in the baseline data between the 2 groups (p > .05). There was significantly less blood loss in the first 24 hours and total blood loss postoperation in the TXA group (p < .01). The surgical wounds healed well after surgery in both groups with no complication. We concluded that topical application of TXA in calcaneal fracture surgeries is a safe and useful method that can reduce postoperative blood loss.

Treatment of Osteosarcoma of the Talus With a 3D-Printed Talar Prosthesis.

A 31-year-old male was diagnosed with osteoblastic osteosarcoma of the talus. Limb-salvage surgery for talar osteosarcoma was performed by replacing the intact talus with a 3D-printed talar prosthesis made from medical-grade titanium. The prosthesis had 3 tunnels for simulating the ligaments around the talus. At the last follow-up, the functional and clinical outcomes were excellent. Our patient achieved 93% restoration of the Musculoskeletal Tumor Society functional score as well as a Toronto Extremity Salvage Score of 93 points, and there was no local recurrence or distant metastasis. A 3D-printed talar prosthesis showed excellent functional and clinical outcomes for a patient with osteosarcoma of the talus. A 3D-printed implant is a feasible option for patients with osteosarcoma of the foot.

HNGF6A Inhibits Oxidative Stress-Induced MC3T3-E1 Cell Apoptosis and Osteoblast Phenotype Inhibition by Targeting Circ_0001843/miR-214 Pathway.

Humanin (HN), a mitochondrial derived peptide, plays cyto-protective role under various stress. In this study, we aimed to investigate the effects of HNGF6A, an analogue of HN, on osteoblast apoptosis and differentiation and the underlying mechanisms. Cell proliferation of murine osteoblastic cell line MC3TC-E1 was examined by CCK8 assay and Edu staining. Cell apoptosis was detected by Annexin V assay under H2O2 treatment. The differentiation of osteoblast was determined by Alizarin red S staining. We also tested the expression of osteoblast phenotype related protein by real-time PCR and Western blot. The interaction between Circ_0001843 and miR-214, miR-214 and TAFA5 was examined by luciferase report assay. Circ_0001843 was inhibited by siRNA and miR-214 was suppressed by miR-214 inhibitor to determine the effects of Circ_0001843 and miR-214 on cell proliferation, apoptosis, and differentiation. HNGF6A, an analogue of HN, exerted cyto-protection and osteogenesis-promotion in MC3T3-E1 cells. The expression of osteoblast phenotype related protein was significantly induced by HNGF6A. Additionally, HNGF6A treatment decreased Circ_0001843 and increased miR-214 levels, as well as inhibited the phosphorylation of p38 and JNK. We further found that Circ_0001843 directly bound with miR-214, which in turn inhibited the phosphorylation of p38 and JNK. Furthermore, both Circ_0001843 overexpression and miR-214 knockdown significantly decreased the cyto-protection and osteogenic promotion of HNGF6A. In summary, our data showed that HNGF6A protected osteoblasts from oxidative stress-induced apoptosis and osteoblast phenotype inhibition by targeting Circ_0001843/miR-214 pathway and the downstream kinases, p38 and JNK.

Ankle Fracture with a Complex Injury Mechanism and Misleading Hook Test Result: A Case Report.

Ankle fractures and their mechanisms of injury can be complex. We report a case of a patient with an uncertain mechanism of injury and an uncommon combination of lower extremity fractures, which fit the criteria for a Lauge-Hansen classification pronation-external-rotation fracture, Maisonneuve fracture, Wagstaffe fracture, and posterior pilon fracture. Plain radiographs and computed tomography scan revealed Chaput tubercle avulsion fractures, an anterior distal fibular fracture fragment, multiple lateral malleolar fractures, a posterior malleolar fracture fragment with proximal displacement, a die-punch fragment between the posterior malleolar fragment and the tibia, a proximal fibular fracture, and possible ankle syndesmotic diastasis. Intraoperative hook test was negative after fixation of the fractures, so syndesmotic fixation was not performed. At 3-month follow-up, plain radiographs showed obvious syndesmotic diastasis. At 1-year follow-up, symptoms persisted and syndesmotic fusion was recommended but declined by the patient. This case demonstrates that both ankle fractures and their mechanisms of injury can be remarkably complex and confusing, posterior pilon fractures can occur along with pronation-external-rotation ankle fractures, syndesmotic fixation should be considered for all patients with Maisonneuve fractures, reliance on the hook test for surgical management decisions may not always be reliable, and there exists a need for a more accurate and reliable intraoperative test to determine the presence of ankle syndesmotic injury.

LRRK1 regulation of actin assembly in osteoclasts involves serine 5 phosphorylation of L-plastin.

Mice with disruption of Lrrk1 and patients with nonfunctional mutant Lrrk1 exhibit severe osteopetrosis phenotypes because of osteoclast cytoskeletal dysfunction. To understand how Lrrk1 regulates osteoclast function by modulating cytoskeleton rearrangement, we examined the proteins that are differentially phosphorylated in wild-type mice and Lrrk1-deficient osteoclasts by metal affinity purification coupled liquid chromatography/mass spectrometry (LC/MS) analyses. One of the candidates that we identified by LC/MS is L-plastin, an actin bundling protein. We found that phosphorylation of L-plastin at serine (Ser) residues 5 was present in wild-type osteoclasts but not in Lrrk1-deficient cells. Western blot analyses with antibodies specific for Ser5 phosphorylated L-plastin confirmed the reduced L-plastin Ser5 phosphorylation in Lrrk1 knockout (KO) osteoclasts. micro computed tomography (Micro-CT) analyses revealed that the trabecular bone volume of the distal femur was increased by 27% in the 16 to 21-week-old L-plastin KO females as compared with the wild-type control mice. The ratio of bone volume to tissue volume and connectivity density were increased by 44% and 47% (both P < 0.05), respectively, in L-plastin KO mice. Our data suggest that targeted disruption of L-plastin increases trabecular bone volume, and phosphorylation of Ser5 in L-plastin in the Lrrk1 signaling pathway may in part contribute to actin assembly in mature osteoclasts.

Locally Produced IGF-1 Promotes Hypertrophy of the Ligamentum Flavum via the mTORC1 Signaling Pathway.

BACKGROUND/AIMS: Narrowing of the lumbar spinal canal is a condition called lumbar spinal stenosis (LSS) and is a high-morbidity problem in the elderly. LSS is commonly caused by hypertrophy of the ligamentum flavum (HLF). Previous studies showed that fibrosis of the ligamentum flavum (LF) largely contributed to HLF. However, the underlying pathomechanism remains unclear. Insulin-like growth factor-1 (IGF-1) is known to have an intimate relationship with fibrosis in various tissues. Nevertheless, currently, there are few studies regarding IGF-1 in HLF. In this study, we investigated the role of IGF-1 in HLF and its potential molecular mechanism of action. METHODS: First, the IGF-1, phosphorylation of IGF-1 receptor (pIGF-1R), phosphorylation of AKT (pAKT), phosphorylation of S6(pS6), collagen I and collagen III expression levels were examined via immunohistochemistry and Western blotting in LF tissues from patients with LSS or Non-LSS. Second, primary LF cells were isolated from adults with a normal LF thickness and were cultured with different concentrations of IGF-1 with or without NVP-AEW541/rapamycin. RESULTS: The results showed that IGF-1, pIGF-1R, pAKT, pS6, collagen I and collagen III protein expression in the LSS group was significantly higher than that in the Non-LSS group. Meanwhile, pIGF-1R, pAKT, pS6, collagen I and collagen III protein expression was significantly enhanced in LF cells after IGF-1 exposure, which can be notably blocked by NVP-AEW541. In addition, pS6, collagen I and collagen III protein expression was blocked by rapamycin. CONCLUSIONS: Enhanced IGF-1 promotes the synthesis of collagen I and collagen III via the mTORC1 signaling pathway, which eventually contributes to hypertrophy of the ligamentum flavum.

Leucine-rich repeat kinase-1 regulates osteoclast function by modulating RAC1/Cdc42 Small GTPase phosphorylation and activation.

Leucine-rich repeat kinase-1 (Lrrk1) consists of ankyrin repeats (ANK), leucine-rich repeats (LRR), a GTPase-like domain of Roc (ROC), a COR domain, a serine/threonine kinase domain (KD), and WD40 repeats (WD40). Previous studies have revealed that knockout (KO) of Lrrk1 in mice causes severe osteopetrosis, and a human mutation of Lrrk1 leads to osteosclerotic metaphysial dysplasia. The molecular mechanism by which Lrrk1 regulates osteoclast function is unknown. In this study, we generated a series of Lrrk1 mutants and evaluated their ability to rescue defective bone resorption in Lrrk1-deficient osteoclasts by use of pit formation assays. Overexpression of Lrrk1 or LRR-truncated Lrrk1, but not ANK-truncated Lrrk1, WD40-truncated Lrrk1, Lrrk1-KD, or K651A mutant Lrrk1, rescued bone resorption function of Lrrk1 KO osteoclasts. We next examined whether RAC1/Cdc42 small GTPases are direct substrates of Lrrk1 in osteoclasts. Western blot and pull-down assays revealed that Lrrk1 deficiency in osteoclasts resulted in reduced phosphorylation and activation of RAC1/Cdc42. In vitro kinase assays confirmed that recombinant Lrrk1 phosphorylated RAC1-GST protein, and immunoprecipitation showed that the interaction of Lrrk1 with RAC1 occurred within 10 min after RANKL treatment. Overexpression of constitutively active Q61L RAC1 partially rescued the resorptive function of Lrrk1-deficient osteoclasts. Furthermore, lack of Lrrk1 in osteoclasts led to reduced autophosphorylation of p21 protein-activated kinase-1 at Ser144, catalyzed by RAC1/Cdc42 binding and activation. Our data indicate that Lrrk1 regulates osteoclast function by directly modulating phosphorylation and activation of small GTPase RAC1/Cdc42 and that its function depends on ANK, ROC, WD40, and kinase domains.

Autologous Costal Chondral/Osteochondral Transplantation and Costa-Derived Chondrocyte Implantation for Articular Cartilage Repair: Basic Science and Clinical Applications.

There has been increasing application of autologous costal chondral/osteochondral transplantation (ACCT/ACOT) and costa-derived chondrocyte implantation (ACCI) for articular cartilage repair over the past three decades. This review presents the major evidence on the properties of costal cartilage and bone and their qualifications as grafts for articular cartilage repair, the major clinical applications, and the risks and strategies for costal chondral/osteochondral graft(s) harvest. First, costal cartilage has many specific properties that help restore the articular surface. Costa, which can provide abundant cartilage and cylindrical corticocancellous bone, preserves permanent chondrocyte and is the largest source of hyaline cartilage. Second, in the past three decades, autologous costal cartilage-derived grafts, including cartilage, osteochondral graft(s), and chondrocyte, have expanded their indications in trauma and orthopaedic therapy from small to large joints, from the upper to lower limbs, and from non-weight-bearing to weight-bearing joints. Third, the rate of donor-site complications of ACCT or ACOT is low, acceptable, and controllable, and some skills and accumulated experience can help reduce the risks of ACCT and ACOT. Costal cartilage-derived autografting is a promising technique and could be an ideal option for articular chondral lesions with or without subchondral cysts. More high-quality clinical studies are urgently needed to help us further understand the clinical value of such technologies.

Comparison of Arthroscopic Microfracture for Osteochondral Lesions of the Talus With and Without Small and Shallow Subchondral Cysts.

BACKGROUND: Whether arthroscopic microfracture is effective in treating cystic osteochondral lesions of the talus (OLTs) remains controversial. In this study, outcome parameters in patients with small and shallow subchondral cysts are compared to patients without cysts with the hypothesis that equivalent outcomes may be found after primary microfracture treatment. METHODS: From 2018 to 2021, all 50 OLTs treated with arthroscopic microfracture in the authors' hospital were retrospectively reviewed for eligibility. Single unilateral symptomatic lesions were included and divided into the cyst and noncyst groups, whereas kissing lesions and arthritic lesions were excluded. Numeric rating scale (NRS) scores, American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot scores, Tegner activity level scores, Foot and Ankle Ability Measure (FAAM) scores, and magnetic resonance (MR) imaging results were used to describe outcomes. RESULTS: A total of 35 patients were included, 16 in the cyst group and 19 in the noncyst group. The patient characteristics were similar between the 2 groups (P > .05). In the cyst group the average cysts depth was 5.0 ± 1.3 mm. After a mean follow-up duration of 36.2 ± 10.2 months, no significant differences were found between the 2 groups in NRS, AOFAS, FAAM, or Tegner score improvement (P > .05). Three patients (19%) in the cyst group had no NRS score improvement. CONCLUSION: OLTs with small and shallow subchondral cysts can be treated with arthroscopic microfracture and achieve similar outcomes as noncystic lesions. A few cystic lesions may not respond to microfracture treatment. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Aligned cryogel fibers incorporated 3D printed scaffold effectively facilitates bone regeneration by enhancing cell recruitment and function.

Reconstructing extensive cranial defects represents a persistent clinical challenge. Here, we reported a hybrid three-dimensional (3D) printed scaffold with modification of QK peptide and KP peptide for effectively promoting endogenous cranial bone regeneration. The hybrid 3D printed scaffold consists of vertically aligned cryogel fibers that guide and promote cell penetration into the defect area in the early stages of bone repair. Then, the conjugated QK peptide and KP peptide further regulate the function of the recruited cells to promote vascularization and osteogenic differentiation in the defect area. The regenerated bone volume and surface coverage of the dual peptide-modified hybrid scaffold were significantly higher than the positive control group. In addition, the dual peptide-modified hybrid scaffold demonstrated sustained enhancement of bone regeneration and avoidance of bone resorption compared to the collagen sponge group. We expect that the design of dual peptide-modified hybrid scaffold will provide a promising strategy for bone regeneration.

Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3.

Extracellular matrix (ECM) stiffening is a typical characteristic of cartilage aging, which is a quintessential feature of knee osteoarthritis (KOA). However, little is known about how ECM stiffening affects chondrocytes and other molecules downstream. This study mimicked the physiological and pathological stiffness of human cartilage using polydimethylsiloxane (PDMS) substrates. It demonstrated that epigenetic Parkin regulation by histone deacetylase 3 (HDAC3) represents a new mechanosensitive mechanism by which the stiffness matrix affected chondrocyte physiology. We found that ECM stiffening accelerated cultured chondrocyte senescence in vitro, while the stiffness ECM downregulated HDAC3, prompting Parkin acetylation to activate excessive mitophagy and accelerating chondrocyte senescence and osteoarthritis (OA) in mice. Contrarily, intra-articular injection with an HDAC3-expressing adeno-associated virus restored the young phenotype of the aged chondrocytes stimulated by ECM stiffening and alleviated OA in mice. The findings indicated that changes in the mechanical ECM properties initiated pathogenic mechanotransduction signals, promoted the Parkin acetylation and hyperactivated mitophagy, and damaged chondrocyte health. These results may provide new insights into chondrocyte regulation by the mechanical properties of ECM, suggesting that the modification of the physical ECM properties may be a potential OA treatment strategy.

Clinical Outcomes of Fusion in Type II Accessory Naviculars With or Without Asymptomatic Flatfeet.

BACKGROUND: Few studies have reported the clinical outcomes of fusion surgeries for type II accessory naviculars. Whether the combination of accessory naviculars and asymptomatic flatfoot will result in worse outcomes in accessory navicular surgeries remains to be elucidated. Our study aims to report the clinical outcomes of fusion for type II accessory naviculars and make a subgroup comparison among accessory navicular patients with or without asymptomatic flatfeet. METHODS: From May 2017 to June 2021, all painful type II accessory naviculars with or without asymptomatic flatfeet in our inpatient center were reviewed, and those who only underwent fusion surgeries were included in the retrospective study. Visual analog scale (VAS) scores, American Orthopaedic Foot & Ankle Society (AOFAS) midfoot scores, Tegner activity level scores, complications, patient-reported satisfaction, and imaging results (Meary angle in the weightbearing lateral view, talo-first metatarsal angle and talonavicular coverage angle in the weightbearing anteroposterior view) were used to describe outcomes. RESULTS: Thirty-two eligible patients responded to the latest follow-up request and were included in this study. The mean follow-up duration was 37.1 ± 16.0 months. The average VAS pain score improved from 4.7 ± 1.8 preoperatively to 0.9 ± 1.2 at the latest follow-up (P<.001). The average AOFAS midfoot score improved from 67.1 ± 8.5 preoperatively to 90.2 ± 10.7 at the latest follow-up (P<.001). The preoperative and postoperative Tegner activity level scores were similar (3.3 ± 1.5 vs 3.5 ± 1.6, P=.136). The overall complication rate was 37.5%. The most common complication was nonunion (31.3%). The overall satisfaction rate was 90.6%. Similar outcomes were observed between the flatfoot and the nonflatfoot subgroups. CONCLUSION: Fusion for painful type II accessory naviculars resulted in good symptom relief, function improvement, and patient satisfaction at midterm follow-up, but the nonunion rate was relatively high. Fusion for painful type II accessory naviculars with or without asymptomatic mild to moderate flatfoot brought about similar clinical outcomes. LEVEL OF EVIDENCE: Level III, retrospective comparative study.