Current Understanding of Osteoarthritis
Understanding of osteoarthritis has greatly evolved in recent years. The disease was once described as a “wear and tear” disorder affecting articular cartilage. This is a gross underestima- tion of the affectation. Evidence now exists showing that osteoarthritis in fact involves many tissues including subchondral bone, mus- cles, and tendons. It is debatable whether the bone involvement is primary or secondary in osteoarthritis.1In addition, the synoviocytes lin- ing the joint capsule appear to be involved in the joint destruction by issuing various cytokines.
Another clear association exists between obesity and osteoarthritis. Obviously, obesity itself might lead to increased mechanical loading of joint surfaces because of both total body weight and alterations in gait patterns. However, obese people tend to be less physically active and, thus, although peak joint forces might be increased, repeated cumulative loads might actually be decreased in obese people as compared with athletic ones. Thus, although it is true that a mechanical relation might be responsible for the cartilage destruction, other factors might also be involved. However, the relationship between osteoarthritis and obesity seems more complex.
Increased levels of fatty acids are found in osteoarthritic cartilage.2 Fatty acids and other metabolites related to obesity could presumably be related to the progression of polyarticular
osteoarthritis, i.e., the generalized form of the disorder as suggested by Aspden et al.3
Furthermore, several studies have docu- mented abnormal bone metabolism in osteoarthritic individuals including altered bone metabolism in remote sites (iliac bone) in patients with hand osteoarthritis.4The disorder in osteoarthritis seems to affect not only bone and cartilage but muscle as well. Although it is debatable whether muscle weakness precedes or follows the joint dysfunction, some authors sug- gest that muscle dysfunction is a primary disor- der in these individuals eventually leading to joint destruction.5
If the above observations are correct, a possi- ble explanation for the affectation of different cell types in these disorders might be a stem cell dysfunction. It is well known that the chondro- cytic, osteoblastic, fibroblastic, and adipocytic lineages share a common stem cell – i.e., the mesenchymal stem cell (MSC). If osteoarthritis is a manifestation of stem cell dysfunction, then manipulated stem cells might be a possible solu- tion to this disorder.
MSCs in Osteoarthritis
What is the role of MSCs in osteoarthritis? Bone marrow contains a subpopulation of cells demonstrating a mesenchymal progenitor cell behavior.6 These cells are capable in vitro of forming both bone and cartilage under the
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Osteoarthritis and Mesenchymal Cells – The Prospects for Repair of the Disease by Cell Transplantation and Tissue Engineering
Dror Robinson
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appropriate environmental conditions. Such cells exist as well in osteoarthritis joints. The fre- quency of the subpopulation of stromal cells that are CD9/CD90/CD166 positive seems to be around 5% in osteoarthritic synovial mem- brane.7These mesenchymal cells appear to be attracted to repair sites of partial-thickness injuries of articular cartilage by transforming growth factor β.8 Although even end-stage osteoarthritis joints contain MSCs,7their activ- ity, both adipogenic and chondrogenic, seems to be reduced as compared with normal joints.9 This conforms to the known increase in osteoblastic activity in osteoarthritic bones, both adjacent to affected joints and in remote sites. It has been shown that osteoblasts from patients with osteoarthritis proliferate in vitro more rapidly than those from healthy individu- als and express different concentrations of markers.10 Implantation of MSCs into osteoarthritic defects in humans during high tibial osteotomy led to improvement in the qual- ity of repair tissue formed in the defects.
However, clinical improvement could not be demonstrated as compared with the group undergoing high tibial osteotomy alone.11 The conclusion from these two studies seems to be that although mesenchymal cells exist in osteoarthritic joints, they appear to be of reduced quality especially with regard to chon- drogenic differentiation. Thus, improvement of clinical results might require an induction of differentiation toward a more typical chondro- genic phenotype. In addition, it seems to be desirable to deliver large numbers of MSCs into osteoarthritic joints. Culture in vitro appears to enrich the culture with cells capable of chondro- osseous differentiation by approximately an order of magnitude.7In osteoarthritic joints in contrast with rheumatoid arthritis, the number of MSCs in the synovium seems to be reduced.12 The difference may be related to the lack of MSC recruitment in osteoarthritis. In contrast, in an experimental arthritis model mimicking rheumatoid arthritis, stem cells were recruited by tumor necrosis factor-α.13 An interesting work by Murphy et al.14has demonstrated that even a scaffold-free approach of delivering bone marrow-derived stem cells can lead to regenera- tion of joint’s injured tissues. In this landmark study, repair of a caprine model of osteoarthri- tis had been enhanced by the use of intraa- rticular injections of a suspension of bone marrow mesenchymal cells and hyaluronic acid.
Osteoarthritis has been induced surgically by resection of both the medial meniscus and the anterior cruciate ligament. In this model, osteo- phyte formation and articular cartilage degener- ation rapidly ensues. The animals were treated by either injection of bone marrow-derived MSCs in hyaluronic acid or hyaluronic acid alone. It is particularly noteworthy that not only was cartilage quality maintained better in the former group, but evidence of medial meniscus regeneration was seen in the MSC-augmented group indicating that also meniscus repair might be improved by MSC addition. It is important to note that this study did not utilize a scaffold for immobilizing the cells in the artic- ular cartilage defect. It is probably not feasible in most clinical situations to fill defects with scaf- folds. In contrast to most experimental situa- tions, clinically encountered focal cartilage defects are large, shallow, and often uncon- tained. An uncontained defect is a defect that is not totally surrounded by articular cartilage.
Such a defect is very difficult to fill with a stable scaffold, because the scaffold has a tendency to displace toward the uncontained side.
Furthermore, most articular cartilage defects in the osteoarthritis joint are so-called “kissing lesions,” i.e., the cartilage is damaged on both sides of the joint at areas that make contact with each other during joint motion. Thus, it is likely that any scaffold placed in “kissing lesions” will tend to be eroded and displaced by joint motion.
This study describes the use of hyaluronan as a cell-delivery vehicle. Hyaluronan is not an inert substance but rather is necessary for granula- tion-tissue production and cell proliferation.
The substance also encourages migration and proliferation of MSCs.14 Thus, it seems that repair of articular cartilage might not require scaffolds to carry the cells but rather addition of stem cells.
Source of Mesenchymal Progenitor Cells
Another question to be answered refers to the source of mesenchymal progenitor cells needed to regain joint homeostasis. The currently accepted technique of autologous chondrocyte implantation seems to involve MSCs. The chon- drocytes undergo dedifferentiation in vitro during cell culture. Some of the cells in these
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cultures appear to be mesenchymal progeni- tors.15The success of this technique depends on implantation of the cells into a cartilage defect and locally mediated signals that induce carti- lage repair and lead to chondrogenic redifferen- tiation of these cells. Recently, it has been shown that synovial fluid contains MSCs.16These seem to be more common in osteoarthritis than in rheumatoid arthritis. The role of these cells in the osteoarthritic process is not clear. It is possi- ble that the cells are just debris released from the injured articular surfaces. However, it is possi- ble that the cells represent a repair attempt gone awry. The latter theory is supported by the clin- ical observation of secondary synovial chondro- matosis, i.e., bone and cartilage formation inside the synovial membrane that might derive from these floating mesenchymal cells. Recently, the sequence of osteophyte formation has been characterized on the histologic and immunohis- tochemical level.17Osteophyte formation begins with mesenchymal condensation, passes through a stage similar to growth plate forma- tion, and ends with a mature osteophyte covered by hyaline-like cartilage. Thus, it seems plausi- ble that MSCs present locally within the diseased joint, are capable of forming synovial chondro- osseous bodies18 as well as forming osteo- phytes,17 but are not capable of repairing the joint surfaces. The locally present MSCs have been termed “niche” stem cells, which are inher- ently more suitable for repair of local tissues.
Unfortunately, it seems that in osteoarthritis these cells malfunction.34It is possible that cells recruited from autologous bone marrow and cultured in vitro could be selected to express a more chondrogenic phenotype and to attach into cartilage defects to allow better repair of joint surfaces without osteophyte formation.
Recently, an exciting new technique of targeting repair cells into damaged joint surfaces has been termed cell painting.20 In this technique, cells are coated by noncytotoxic antibodies that allow site-specific attachment to damaged cartilagi- nous surfaces. The solution to the osteoarthritic enigma might be related to selective prolifera- tion of stem cells in culture, selecting for the chondrogenic phenotype at the expense of the osteogenic phenotype and later delivering the cells locally into the joint allowing matrix-spe- cific binding of the cells so that they will con- centrate at damaged areas instead of the joint periphery. There is some evidence that articular cartilage in osteoarthritis contains MSCs, possi-
bly derived from bone marrow. The cells in bone marrow capable of chondrocytic differentiation coexpress CD105 and CD166.21 CD105 is endoglin, a type of transforming growth factor β receptor (III). CD166 is activated leukocyte cell adhesion molecule. Cells expressing CD166 in the perichondrium are capable of generating MSCs.22 Coexpression of these two antigens appears to indicate a subpopulation of mes- enchymal stem cells capable of generating carti- lage-like tissue. A recent study has shown that osteoarthritic cartilage contains more MSCs than normal cartilage.21It is possible that cur- ing osteoarthritis could involve addition of mesenchymal progenitors and encouragement of the cells to undergo differentiation into cartilage.
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