Klf10 is involved in extracellular matrix calcification of chondrocytes alleviating chondrocyte senescence.

Osteoarthritis (OA) is a chronic degenerative disease resulting joint disability and pain. Accumulating evidences suggest that chondrocyte extracellular matrix calcification plays an important role in the development of OA. Here, we showed that Krüppel-like factor 10 (Klf10) was involved in the regulation of chondrocyte extracellular matrix calcification by regulating the expression of Frizzled9. Knockdown of Klf10 attenuated TBHP induced calcification and reduced calcium content in chondrocytes. Restoring extracellular matrix calcification of chondrocytes could aggravate chondrocyte senescence. Destabilization of a medial meniscus (DMM) mouse model of OA, in vivo experiments revealed that knockdown Klf10 improved the calcification of articular cartilage and ameliorated articular cartilage degeneration. These findings suggested that knockdown Klf10 inhibited extracellular matrix calcification-related changes in chondrocytes and alleviated chondrocyte senescence.

Inhibition of Klf10 Attenuates Oxidative Stress-Induced Senescence of Chondrocytes via Modulating Mitophagy.

Osteoarthritis (OA) is the most prevalent degenerative joint disease in the elderly. Accumulation of evidence has suggested that chondrocyte senescence plays a significant role in OA development. Here, we show that Krüppel-like factor 10 (Klf10), also named TGFß inducible early gene-1 (TIEG1), is involved in the pathology of chondrocyte senescence. Knocking down the Klf10 in chondrocytes attenuated the tert-butyl hydroperoxide (TBHP)-induced senescence, inhibited generation of reactive oxygen species (ROS), and maintained mitochondrial homeostasis by activating mitophagy. These findings suggested that knocking down Klf10 inhibited senescence-related changes in chondrocytes and improved cartilage homeostasis, indicating that Klf10 may be a therapeutic target for protecting cartilage against OA.

A Novel Role for RILP in Regulating Osteoclastogenesis and Bone Resorption.

Increased bone resorption caused by excessive number or activity of osteoclasts is the main cause of osteoporosis. Osteoclasts are multinucleated cells that are formed by the fusion of precursor cells. Although osteoclasts are primarily characterized by bone resorption, our understanding of the mechanisms that regulate the formation and function of osteoclasts is poor. Here we showed that the expression level of Rab interacting lysosomal protein (RILP) was strongly induced by receptor activator of NF-κB ligand in mouse bone marrow macrophages. Inhibition of RILP expression induced a drastic decrease in the number, size, F-actin ring formation of osteoclasts, and the expression level of osteoclast-related genes. Functionally, inhibition of RILP reduced the migration of preosteoclasts through PI3K-Akt signaling and suppressed bone resorption by inhibiting the secretion of lysosome cathepsin K. Treatments with siRNA-RILP attenuated pathologic bone loss in disease models induced by lipopolysaccharide. Thus, this work indicates that RILP plays an important role in the formation and bone resorption function of osteoclasts and may have a therapeutic potential to treat bone diseases caused by excessive or hyperactive osteoclasts.

Inhibition of Cpt1a alleviates oxidative stress-induced chondrocyte senescence via regulating mitochondrial dysfunction and activating mitophagy.

Osteoarthritis (OA) is an age-related chronic degenerative disease, and chondrocyte senescence has been established to play an important role in the pathological process. There is ample evidence to suggest that lipid metabolism plays an important role in the aging process. However, the effect of lipid metabolism on chondrocyte senescence and OA remains unclear. Accordingly, we constructed a TBHP-induced senescent chondrocytes model and a destabilization of the medial meniscus (DMM) mouse model. We found that lipid accumulation and fatty acid oxidation were enhanced in senescent chondrocytes. Interestingly, carnitine palmitoyltransferase 1A (Cpt1a), the rate-limiting enzyme for fatty acid oxidation, was highly expressed in senescent chondrocytes and murine knee cartilage tissue. Suppressing Cpt1a expression using siRNA or Etomoxir, an inhibitor of Cpt1a, could attenuate oxidative stress-induced premature senescence and OA phenotype of primary murine chondrocytes, decrease cellular ROS levels, restore mitochondrial function, and maintain mitochondrial homeostasis via activating mitophagy. In vivo, pharmacological inhibition of Cpt1a by Etomoxir attenuated cartilage destruction, relieved joint space narrowing and osteophyte formation in the DMM mouse model. Overall, these findings suggested that knockdown of Cpt1a alleviated chondrocyte senescence by regulating mitochondrial dysfunction and promoting mitophagy, providing a new therapeutic strategy and target for OA treatment.

TGF-ß1 regulates chondrocyte proliferation and extracellular matrix synthesis via circPhf21a-Vegfa axis in osteoarthritis.

BACKGROUND: The transforming growth factor-beta (TGF-ß) signaling pathway is an important pathway associated with the pathogenesis of osteoarthritis (OA). This study was to investigate the involvement of circRNAs in the TGF-ß signaling pathway. METHODS: Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2'-deoxyuridine (EdU) assay were used to detect the proliferation of primary mouse chondrocytes (PMCs). RNA-sequencing together with bioinformatics analysis were used to systematically clarify TGF-ß1 induced alternations of circRNAs in PMCs. The regulatory and functional role of circPhf21a was examined in PMCs. Downstream targets of circPhf21a were explored by RNA-sequencing after overexpression of circPhf21a and verified by RT-qPCR in PMCs. Finally, the role and mechanism of circPhf21a in OA were explored in mouse models. RESULTS: We found that TGF-ß1 promoted the proliferation of PMCs. Meanwhile, RT-qPCR and western blotting indicated that TGF-ß1 promoted extracellular matrix (ECM) anabolism. RNA-sequencing revealed that a total of 36 circRNAs were differentially expressed between PMCs treated with and without TGF-ß1. Of these, circPhf21a was significantly decreased by TGF-ß1. Furthermore, circPhf21a knockdown promoted the proliferation and ECM synthesis of PMCs, whereas overexpression of circPhf21a showed the opposite effects. Mechanically, the expression profiles of the mRNAs revealed that Vegfa may be the target of circPhf21a. Additionally, we found that circPhf21a was significantly upregulated in the mouse OA model, and inhibition of circPhf21a significantly relieved the progression of OA. CONCLUSIONS: Our results found that TGF-ß1 promoted the proliferation and ECM synthesis of PMCs via the circPhf21a-Vegfa axis, which may provide novel therapeutic targets for OA treatment. Video abstract.

Modified F configuration in the treatment of Pauwels type III femoral neck fracture: a finite element analysis.

BACKGROUND: The optimal treatment of Pauwels type III femoral neck fracture (FNF) in young patients remains a worldwide challenge in orthopedic surgery. METHODS: Finite element models of four internal fixations were developed to treat Pauwels type III FNF: a: the traditional inverted triangular parallel cannulated screw (PCS) model, b: the F-technique cannulated screw model, c: the modified F-technique cannulated screw model using a fully threaded screw instead of a partially threaded distally, d: the dynamic hip screw coupled with derotational screw (DHS + DS) model. Under the same conditions, finite element analyses were carried out to compare the displacement and von Mises stress distribution of four internal fixations and femurs, the maximum crack distances of the fracture surfaces, Z axis displacements of four models as well as the stress distribution in the subtrochanteric region. RESULTS: The modified F-technique configuration resulted in a more stable fixation as compared to the other three configurations, with respect to the maximum displacement and stress peaks of femur and internal fixations, the maximum crack distances of the fracture surfaces, Z axis displacements of four configurations as well as the stress distribution in the subtrochanteric region. CONCLUSIONS: Our results suggested that modified F-technique configuration show a better performance in resisting shearing and rotational forces in treating Pauwels type III FNF compared to those using traditional inverted triangular PCS, the F-technique configuration or DHS + DS, providing a new choice for the treatment of FNFs.

Ramp lesion of the medial meniscus.

Ramp lesion of the medial meniscus used to be completely disregarded in the past.Ramp lesion has been now put under the spotlight by orthopaedic and sport medicine surgeons and requires attention.It is closely associated with anterior cruciate ligament injury. Major risk factors include chronic laxity, lateral meniscal lesion, anterior cruciate ligament reconstruction revision, anterolateral ligament tear concomitant with anterior cruciate ligament injury, time from injury, pre-operative side-to-side laxity > 6 mm, age < 30 years old, male sex, etc.Radiologists attempt to create diagnostic criteria for ramp lesion using magnetic resonance imaging. However, the only definite method to diagnose ramp lesion is still arthroscopy. Various techniques exist, among which posteromedial approach is the most highly recommended.Various treatment options are available. The success rate of ramp repair is very high. Major complications are uncommon. Cite this article: EFORT Open Rev 2021;6:372-379. DOI: 10.1302/2058-5241.6.200126.