In clinical practice, repairing osteochondral defects presents a challenge due to the varying biological properties of articular cartilages and subchondral bones. Thus, elucidating how spatial microenvironment‐specific biomimetic scaffolds can be used to simultaneously regenerate osteochondral tissue is an important research topic. Herein, a novel bioinspired double‐network hydrogel scaffold produced via 3D printing with tissue‐specific decellularized extracellular matrix (dECM) and human adipose mesenchymal stem cell (MSC)‐derived exosomes is described. The bionic hydrogel scaffolds promote rat bone marrow MSC attachment, spread, migration, proliferation, and chondrogenic and osteogenic differentiation in vitro, as determined based on the sustained release of bioactive exosomes. Furthermore, the 3D‐printed microenvironment‐specific heterogeneous bilayer scaffolds efficiently accelerate the simultaneous regeneration of cartilage and subchondral bone tissues in a rat preclinical model. In conclusion, 3D dECM‐based microenvironment‐specific biomimetics encapsulated with bioactive exosomes can serve as a novel cell‐free recipe for stem cell therapy when treating injured or degenerative joints. This strategy provides a promising platform for complex zonal tissue regeneration whilst holding attractive clinical translation potential.

Meniscus deficiency, the most common and refractory disease in human knee joints, often progresses to osteoarthritis (OA) due to abnormal biomechanical distribution and articular cartilage abrasion. However, due to its anisotropic spatial architecture, complex biomechanical microenvironment, and limited vascularity, meniscus repair remains a challenge for clinicians and researchers worldwide. In this study, we developed a 3D printing-based biomimetic and composite tissue-engineered meniscus scaffold consisting of polycaprolactone (PCL)/silk fibroin (SF) with extraordinary biomechanical properties and biocompatibility. We hypothesized that the meticulously tailored composite scaffold could enhance meniscus regeneration and cartilage protection.

Emerging evidence suggests that osteoarthritis is associated with high cholesterol levels in some osteoarthritis patients. However, the specific mechanism under this metabolic osteoarthritis phenotype remains unclear. We find that cholesterol metabolism-related gene, LRP3 (low-density lipoprotein receptor-related protein 3) is significantly reduced in high-cholesterol diet mouse’s cartilage. By using Lrp3^−/− mice in vivo and LRP3 lentiviral-transduced chondrocytes in vitro, we identify that LRP3 positively regulate chondrocyte extracellular matrix metabolism, and its deficiency aggravate the degeneration of cartilage. Regardless of diet, LRP3 overexpression in cartilage attenuate anterior cruciate ligament transection induced osteoarthritis progression in rats and Lrp3 knockout-induced osteoarthritis progression in mice. LRP3 knockdown upregulate syndecan-4 by activating the Ras signaling pathway. We identify syndecan-4 as a downstream molecular target of LRP3 in osteoarthritis pathogenesis. These findings suggest that cholesterol-LRP3- syndecan-4 axis plays critical roles in osteoarthritis development, and LRP3 gene therapy may provide a therapeutic regimen for osteoarthritis treatment.

Introduction: Extracellular matrix (ECM) degradation leads to malfunction of the cartilage in osteoarthritis (OA). Inflammatory cytokine interleukin-1 beta (IL-1β) functions in ECM degradation and prevents ECM synthesis by down-regulating the key transcription factor, Sox9, and consequently inhibiting ECM gene expression. Evidence reveals that microRNAs (miRNA) have been associated with OA, but little is known of their function in chondrocyte ECM degradation. This study aimed to identify possible miRNAs that mediate IL-1β-induced down-regulation of Sox9 as well as its known down-stream genes, collagen type II and aggrecan. Methods: The miRNAs were predicted based on three classical databases. The expression levels of the predicted miRNAs were assessed in IL-1β stimulated chondrocytes by real-time PCR. A luciferase reporter was used to test the binding of the miRNAs to the 3' untranslated regions (3'UTR) of Sox9. The predicted miRNAs were transfected into chondrocytes to validate their relationship with Sox9. Functional analysis of the miRNAs on chondrocytes ECM degradation was performed at both the mRNA and protein levels after miRNA transfection and IL-1β treatment. Results: Six miRNAs were predicted to target Sox9, and their expression in IL-1β-stimulated chondrocytes was revealed by real-time PCR. The luciferase reporter assay indicated that only miR-101 could bind to the 3'UTR of Sox9. The expression of Sox9 was likewise negatively regulated by miR-101 in rat chondrocytes. Functional analysis showed that miR-101 could aggravate chondrocyte ECM degradation, whereas miR-101 inhibition could reverse IL-1β-induced ECM degradation. Conclusion: miR-101 participates in IL-1β-induced chondrocyte ECM degradation. Down-regulating miR-101 expression can prevent the IL-1β-induced ECM degradation in chondrocytes. miR-101 probably functions by directly targeting Sox9 mRNA.

Mesenchymal stem cells (MSCs) are regarded as a promising cell-based therapeutic tool for tendon repair. This study aimed to compare the different tenogenic differentiation capacities of the three types of MSCs in the presence of bone morphogenic protein 12 (BMP-12). MSCs were isolated from rat bone marrow (BM), inguinal adipose tissue (AD), and synovium (SM) from the knee joint. MSCs were characterized by morphology, proliferation, trilineage differentiation, and surface marker analysis. Tenogenic differentiation potential was initially assessed using real-time polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay in vitro. Histological assessments were also performed after subcutaneous implantation of BMP-12 recombinant adenovirus-infected MSCs in nude mice in vivo. The three types of MSCs exhibited similar fibroblast-like morphology and surface markers but different differentiation potentials toward adipogenic, osteogenic, and chondrogenic lineage fates. Bone marrow-derived MSCs (BM-MSCs) showed the most superior in vitro tenogenic differentiation capacity, followed by synovial membrane-derived MSCs (SM-MSCs) and then adipose-derived MSCs (AD-MSCs). After implantation, all three types of MSC masses infected with BMP-12 recombinant adenovirus emerged in the form of fiber-like matrix, especially in 6-week specimens, compared with the control MSCs in vivo. BM-MSCs and SM-MSCs revealed more intense staining for collagen type I (Col I) compared with AD-MSCs. Differences were not observed between BM-MSCs and SM-MSCs. However, SM-MSCs demonstrated higher proliferation capacity than BM-MSCs. BM-MSCs exhibited the most superior tenogenic differentiation capacity, followed by SM-MSCs. By contrast, AD-MSCs demonstrated the inferior capacity among the three types of MSCs in the presence of BMP-12 both in vivo and in vitro.