Schematic demonstration of different layers of articular (hyaline) cartilage and subchondral bone of human knee joint. Arrows indicate the outermost layer of articular (hyaline) cartilage, that is, the lamina splendens. In some literature, the lamina splendens is also referred to as “the surface zone.” The superficial zone contains thin collagen fibrils and the middle zone contains thin and thick collagen fibrils; the deep zone contains thick collagen fibrils and is, therefore, the most stress-resistant. (A). Traditional concepts suggest that the superficial/gliding zone contains collagen fibrils parallel to the surface of healthy hyaline cartilage (whereas the lamina splendens does not contain collagen fibrils and chondrocytes); (B). Current findings indicate that the superficial/gliding zone contains collagen fibrils oblique to the surface of healthy hyaline cartilage (and the lamina splendens contain interwoven collagen bundles, which are not shown in this figure). Notably, interwoven collagen bundles within the lamina splendens rarely integrate obliquely oriented collagen fibrils in the superficial zone, which implies no tight connection between the two layers. Such a feature provides limited resistance to tearing/peeling off this surface layer from underlying cartilage tissues during exercise/sports accidents.

credit:Intra-Articular Mesenchymal Stem Cell Injection for Knee Osteoarthritis: Mechanisms and Clinical Evidence

Osteoarthritis of the knee (KOA) is characterized by degeneration of the knee cartilage and hyperplasia of the subchondral bone as the main pathological features. The main clinical manifestations are knee joint pain, swelling and activity limitation, which seriously affects the quality of life of patients and has a high disability rate. Cartilage degeneration is the most typical pathological feature of KOA, which is closely related to chondrocyte apoptosis and extracellular matrix degradation. Currently, non-surgical treatments for KOA cannot stop or reverse the process of KOA. Patients with advanced KOA can be treated with artificial knee replacement, but artificial knee replacement has problems such as high treatment cost and many complications[1]. With the deepening of MSC research, it is found that MSC has unique advantages in repairing cartilage damage, and joint cavity injection of MSC is expected to become an important therapy for KOA. Exosomes are the main effective components of MSC in repairing cartilage injury, and they have the advantages of easy collection and storage, good stability, strong targeting and low immune rejection, which have great potential for application in the field of tissue repair[2].

EXO is a 40-150 nm diameter multivesicular vesicle secreted by cells, which can be stabilized in a variety of body fluids, secretion fluids and cell culture media, and plays an important role in paracrine secretion. MSC-EXO contains nucleic acids (mRNA, miRNA, etc.), proteins, lipids and other substances, and has some physiological functions of MSC, such as promoting cartilage regeneration [3]. MSC-EXO can be obtained from bone marrow, adipose, umbilical cord and other tissues. The composition of MSC-EXO from different sources varies, but transmembrane proteins such as apoptosis-related gene 2 interacting protein X, tumor susceptibility gene 101, and CD9, CD63, or CD81 are more conserved in MSC-EXO, and they are often used as the marker proteins of MSC-EXO [4].

One of the mechanisms of action of MSC-EXO in repairing KOA cartilage damage is the inhibition of cartilage ECM degradation. Matrix metalloproteinase (MMP) is one of the important proteases for ECM degradation and plays a key role in cartilage damage. Rilla et al. [5] found that MSC-EXO could reduce the activity of MMP-13, and then inhibit the degradation of cartilage ECM. He et al. [6] found that bone marrow MSC-EXO injected into the knee joint cavity of KOA rats could be endocytosed by chondrocytes, which increased the content of collagen II and proteoglycan and decreased the expression of MMP-13 and polyprotein polyglucosidase in cartilage tissue. This suggests that bone marrow MSC-EXO can effectively promote the synthesis of cartilage extracellular matrix and repair cartilage damage.

In addition, MSC-EXO can inhibit chondrocyte apoptosis and promote chondrocyte proliferation. Zhou et al [7] found that injection of bone marrow MSC-EXO in KOA mice could reduce the symptoms of KOA, and further analysis of the mechanism showed that bone marrow MSC-EXO was able to promote the proliferation of chondrocytes through the bone morphogenetic protein 4 signaling pathway, which in turn slowed down the progression of KOA. Wang et al. [8] found that bone marrow MSC-EXO could inhibit the activation of Wnt pathway by suppressing the expression of calreticulin-11 in chondrocytes, thus promoting chondrocyte proliferation and inhibiting chondrocyte apoptosis.

1. Wei P, Bao R. Intra-Articular Mesenchymal Stem Cell Injection for Knee Osteoarthritis: Mechanisms and Clinical Evidence. Int J Mol Sci. 2022 Dec 21;24(1):59.

2. Giorgino R, Albano D, Fusco S, Peretti GM, Mangiavini L, Messina C. Knee Osteoarthritis: Epidemiology, Pathogenesis, and Mesenchymal Stem Cells: What Else Is New? An Update. Int J Mol Sci. 2023 Mar 29;24(7):6405.

3. Cao Z, Liu W, Qu X, Bi H, Sun X, Yu Q, Cheng G. miR-296-5p inhibits IL-1β-induced apoptosis and cartilage degradation in human chondrocytes by directly targeting TGF-β1/CTGF/p38MAPK pathway. Cell Cycle. 2020 Jun;19(12):1443-1453.

4. Álvarez-Viejo M. Mesenchymal stem cells from different sources and their derived exosomes: A pre-clinical perspective. World J Stem Cells. 2020 Feb 26;12(2):100-109.

5. Rilla K, Mustonen AM, Arasu UT, Härkönen K, Matilainen J, Nieminen P. Extracellular vesicles are integral and functional components of the extracellular matrix. Matrix Biol. 2019 Jan;75-76:201-219.

6. He L, He T, Xing J, Zhou Q, Fan L, Liu C, Chen Y, Wu D, Tian Z, Liu B, Rong L. Bone marrow mesenchymal stem cell-derived exosomes protect cartilage damage and relieve knee osteoarthritis pain in a rat model of osteoarthritis. Stem Cell Res Ther. 2020 Jul 10;11(1):276.

7. Zhou X, Liang H, Hu X, An J, Ding S, Yu S, Liu C, Li F, Xu Y. BMSC-derived exosomes from congenital polydactyly tissue alleviate osteoarthritis by promoting chondrocyte proliferation. Cell Death Discov. 2020 Dec 10;6(1):142.

8. Wang S, Ding P, Xia X, Chen X, Mi D, Sheng S, Gu F, Li Z, Su K, Li Y. Bugan Rongjin decoction alleviates inflammation and oxidative stress to treat the postmenopausal knee osteoarthritis through Wnt signaling pathway. Biomed Eng Online. 2021 Oct 13;20(1):103.