Simultaneous Regulation of the Mechanical/Osteogenic Capacity of Brushite Calcium Phosphate Cement by Incorporating with Poly(ethylene glycol) Dicarboxylic Acid.

Brushite calcium phosphate cement (brushite CPC) is a prospective bone repair material due to its ideal resorption rates in vivo. However, the undesirable mechanical property and bioactivity limited its availability in clinic application. To address this issue, incorporating polymeric additives has emerged as a viable solution. In this study, poly(ethylene glycol) dicarboxylic acid, PEG(COOH), was synthesized and employed as the polymeric additive. The setting behavior, anti-washout ability, mechanical property, degradation rate, and osteogenic capacity of brushite CPC were regulated by incorporating PEG(COOH). The incorporation of PEG(COOH) with carboxylic acid groups demonstrated a positive effect on both mechanical properties and osteogenic activity in bone repair. This study offers valuable insights and suggests a promising strategy for the development of materials in bone tissue engineering.

Correlation Between Preoperative and Postoperative Alignment and Kinematic Gait in Total Knee Arthroplasty.

Objective: Maintaining the lower limb in a neutral posture following total knee arthroplasty (TKA) has long been a concept maintained by operators. This study aimed to investigate the relationship between changes in lower limb alignment and the dynamics of knee gait before and after TKA to understand the impact of alignment on gait better and offer a theoretical foundation for correcting lower limb alignment in TKA. Methods: Our study included a group of 20 participants. The cohort consisted of 1 male and 19 females, 11 left and 9 right knees, ages 58 to 81. Using the Opti_Knee® Knee Motion Test System with infrared reflective markers and a high-speed camera, the step length and 6 degrees of freedom of the knee were recorded. Following that, we investigated the association between HKA angle and knee kinematic gait before and after surgery. Results: For preoperative HKA angles ranging from -28° to -3°, we observed increased step length, flexion-extension rotation, and varus-valgus rotation with an increase in HKA angle. Conversely, an increase in HKA angle from -3 ° to 15° corresponded with decreased step length, flexion-extension rotation, and varus-valgus rotation. An increase in HKA angle from 1° to 3° postoperatively increased step length, flexion-extension rotation, and varus-valgus rotation. In contrast, increasing the HKA angle from 3° to 5° resulted in less flexion-extension rotation. The flexion-extension rotation was at its maximum when the HKA angle was 3°. A 3° postoperative varus resulted in improved kinematic gait. Step length, varus-valgus rotation, and flexion-extension rotation increased with increasing HKA angle in the neutral alignment group. In contrast, the non-neutral alignment group exhibited decreased flexion-extension rotation as the HKA angle increased, while step length and varus-valgus rotation increased as the HKA angle increased. The varus-valgus rotation was statistically significant (P < .05) in the preoperative versus early postoperative period in the 6 degrees of freedom. Conclusions: A 3° varus alignment was found to have a superior postoperative knee kinematic gait, implying that a 3° varus alignment may be more suitable as a new gold standard for TKA than the traditional "0°" alignment. The neutral alignment group demonstrated a better knee kinematic gait than the non-neutral alignment group. During early postoperative walking, significant improvements in varus-valgus rotation were found in the 6 degrees of knee freedom.

Trim21 depletion alleviates bone loss in osteoporosis via activation of YAP1/ß-catenin signaling.

Despite the diverse roles of tripartite motif (Trim)-containing proteins in the regulation of autophagy, the innate immune response, and cell differentiation, their roles in skeletal diseases are largely unknown. We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast (OB) differentiation in osteosarcoma. However, how Trim21 contributes to skeletal degenerative disorders, including osteoporosis, remains unknown. First, human and mouse bone specimens were evaluated, and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients. Next, we found that global knockout of the Trim21 gene (KO, Trim21-/-) resulted in higher bone mass compared to that of the control littermates. We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and elevating the activity of OBs; moreover, Trim21 depletion suppressed osteoclast (OC) formation of RAW264.7 cells. In addition, the differentiation of OCs from bone marrow-derived macrophages (BMMs) isolated from Trim21-/- and Ctsk-cre; Trim21f/f mice was largely compromised compared to that of the littermate control mice. Mechanistically, YAP1/ß-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs. More importantly, the loss of Trim21 prevented ovariectomy (OVX)- and lipopolysaccharide (LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling. Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption, thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.

Saponin from Platycodi radix inactivates PI3K/AKT signaling pathway to hinder colorectal cancer cell proliferation, invasion, and migration through miR-181c/d-5p/RBM47.

Colorectal cancer (CRC) is the third frequent cancer and second leading reason of cancer-related mortality all over the globe. Saponins from Platycodi radix (SPR) and microRNAs (miRNAs) have been reported to regulate CRC cell progression. Real-time quantitative polymerase chain reaction (RT-qPCR) detected miR-181c-5p, miR-181d-5p, and RBM47 expression level. Cell counting kit-8 (CCK-8), 5-ethynyl-20-deoxyuridine (EdU), colony formation, transwell, and wound healing assays validated that miR-181c-5p and miR-181d-5p promote CRC cell proliferation, migration and invasion and SPR exerts opposite effects. Cignal Finder Reporter Array and western blot proved that the activity of PI3K/AKT pathway was decreased by RBM47 overexpression. RNA pulldown, luciferase reporter, and RNA-binding protein immunoprecipitation (RIP) assays proved the interaction between miR-181c/d-5p and RBM47, and RBM47 and PTEN. Rescue experiments were carried out to validate that RBM47 reverses the influence of miR-181c/d-5p on the progression of CRC cells. The stability of PTEN was probed by real-time quantitative polymerase chain reaction in CRC cells treated with Actinomycin D (Act D). To be concluded, SPR inactivates PI3K/AKT signaling pathway to suppress CRC cell proliferation, invasion, and migration via miR-181c/d-5p/RBM47. Elucidating the mechanisms of SPR underlying CRC may offer novel insight into CRC treatment.

Senescent skeletal cells cross-talk with synovial cells plays a key role in the pathogenesis of osteoarthritis.

Osteoarthritis (OA) has been recognized as an age-related degenerative disease commonly seen in the elderly that affects the whole "organ" including cartilage, subchondral bone, synovium, and muscles. An increasing number of studies have suggested that the accumulation of senescent cells triggering by various stresses in the local joint contributes to the pathogenesis of age-related diseases including OA. In this review, we mainly focus on the role of the senescent skeletal cells (chondrocytes, osteoblasts, osteoclasts, osteocyte, and muscle cells) in initiating the development and progression of OA alone or through cross-talk with the macrophages/synovial cells. Accordingly, we summarize the current OA-targeted therapies based on the abovementioned theory, e.g., by eliminating senescent skeletal cells and/or inhibiting the senescence-associated secretory phenotype (SASP) that drives senescence. Furthermore, the existing animal models for the study of OA from the perspective of senescence are highlighted to fill the gap between basic research and clinical applications. Overall, in this review, we systematically assess the current understanding of cellular senescence in OA, which in turn might shed light on the stratified OA treatments.

YAP/miR-524-5p axis negatively regulates TXNIP expression to promote chondrosarcoma cell growth.

Chondrosarcoma (CHS) is the second most common bone malignant tumor and currently has limited treatment options. We have recently demonstrated that thioredoxin interacting protein (TXNIP) plays a crucial role in the oncogenesis of bone sarcoma, yet its implication in CHS is underdetermined. In the present study, we first found that knockdown of TXNIP promotes the proliferation of CHS cell largely through increasing their glycolytic metabolism, which is well-known as Warburg effect for providing energy. Consistent with our previous report that YAP is fundamental for CHS cell growth, herein we revealed that YAP functioned as an upstream molecule of TXNIP, and that YAP negatively regulated TXNIP mRNA and protein expression both in vitro and in vivo. Mechanistically, although knockdown of YAP upregulated both the nuclear and cytoplasmic TXNIP expression, we did not observe any obvious interaction between YAP and TXNIP; instead, miRNA-524-5p was demonstrated to be required for YAP-regulated TXNIP expression and thus controlling CHS cell growth. Together, our study reveals that TXNIP is a tumor suppressor in terms of CHS, and that the YAP/miRNA-524-5p/TXNIP signaling axis may provide a novel clue for CHS targeted therapy.

Investigation of normal knees kinematics in walking and running at different speeds using a portable motion analysis system.

Walking and running at different speeds are common in daily life. This study investigated 6 degrees of freedom (DOF) kinematics of normal knees of Chinese during walking and running. Forty healthy participants were investigated in 4 conditions: comfortable walking, normal walking, slow running and ordinary running. The range of motion (ROM) and peak values in 6 DOF kinematics were analysed. As the speed increased, a general increase in flexion, lateral and proximal translations occurred. Significant increases of ROM in flexion/extension, axial rotation and medial/lateral translations were observed. The ROM of adduction/abduction, anterior/posterior and proximal/distal translations were greatest during normal walking. The maximum and minimum flexion/extension, maximum internal rotation and tibial lateral translations increased with the increase of speed. The maximum and minimum tibial proximal translations in running were found being greater than walking. A phenomenon between walking and running was observed: both tibial proximal/distal and medial/lateral translations increased when changed from walking to running. Non-linear transition exists in 6 DOF kinematics during walking to running. Discoveries in this study may have potential clinical values to serve as references of normal walking and running in the management of knee injury and knee rehabilitation.

Sequential targeting of YAP1 and p21 enhances the elimination of senescent cells induced by the BET inhibitor JQ1.

Chondrosarcoma (CHS) is the second most common bone malignancy with limited therapeutic approaches. Our previous study has found that Yes associated protein 1 (YAP1) is downregulated in CHS cells treated with bromodomain and extraterminal domain (BET) inhibitor JQ1. However, the precise role of YAP1 in CHS is largely unknown. Herein, we found that YAP1 expression was upregulated in CHS tissues, and positively correlated with its grading score. Loss of YAP1 inhibited CHS proliferation and induced cellular senescence, while expression of YAP1 mutants revealed YAP1/TEA domain family member (TEAD)-dependent negative regulation of p21 and subsequent cellular senescence. These results were validated by in vivo experiments using stable shYAP1 cell lines. Mechanistically, negative regulation of p21 by YAP1 occurred post-transcriptionally via Dicer-regulated miRNA networks, specifically, the miR-17 family. Furthermore, we demonstrated that sequential targeting of YAP1 and p21 enhanced the elimination of JQ1-induced senescent cells in a Bcl-2-like 1 (Bcl-XL)/Caspase-3 dependent manner. Altogether, we unveil a novel role of YAP1 signaling in mediating CHS cell senescence and propose a one-two punch approach that sequentially targets the YAP1/p21 axis to eliminate senescent cells.