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 - Cell Therapy Approaches

Osteoarthritis (OA), also known as degenerative joint disease or degenerative arthritis, is a medical condition characterized by degradation of joint articular cartilage and subchondral bone. The disease is usually associated with the synovial joint. The primary cause of OA is usually mechanical stress applied to the articular cartilage combined with its inability to self-repair. The mechanical damage can be a result of injury, loss of muscular strength supporting the joint, aging, or alternatively low levels of local inflammation associated with trauma or obesity. OA can also be secondary to specific types of inherited genetic disorders. The main joints affected by osteoarthritis are weight-bearing joints such as knees and hips, but also those of the fingers, feet and spine. Essentially, any joint in the body can be affected by OA.

Regardless of the primary cause of the osteoarthritis, modifications in the intra-joint environment lead to inability of the joint tissue cells to produce healthy extracellular matrix essential for articular cartilage and joint integrity. Instead, the joint cells produce different type of matrix that is unable to properly resist mechanical load. Moreover, at the early stages of OA these modifications trigger production of molecules, such as metalloproteinases, aggrecanases and pro-inflammatory cytokines, leading to progressive cartilage degradation. The condition is further aggravated upon release of cartilage components to the synovial fluid, consequently triggering local inflammation. Osteoarthritis patients suffer from pain in a joint area, stiffness, tenderness, and sometimes from joint effusion leading to impaired joint movement and compromised physical activity.

Cell Therapy Approaches

The main obstacle in cartilage repair is its inability to regenerate due to its avascular structure. Progenitor cells from the blood, bone marrow or even from the adjacent surrounding matrix have no route to access the lesions and secrete the reparative matrix. Today, the standard therapy for osteoarthritis exploits anti-inflammatory pharmacological agents and surgical intervention, including cell transplantation or injection in attempt to achieve cartilage regeneration in vivo.

There are three main types of surgical procedures currently accepted in clinics:

Bone Marrow (BM) stimulation – aimed to induce the BM chondro-progenitors and to enhance cytokine production, achieved by drilling, abrasion or micro-fracture of the bone region adjacent to the defective cartilage. A very limited number of progenitor cells is typically induced by this procedure.

Mosaicplasty – transplantation of autologous osteochondral plugs into the cartilage lesion, resulting in formation of hyaline cartilage. Since the availability of autologous plugs is extremely limited, large cartilage defects cannot be cured by this method.

Autologous Chondrocyte Implantation (ACI)chondrocytes from the patient obtained by biopsy and expanded in culture are injected back to the lesion site and covered by a periosteal flap. In the past decade, second-generation ACI methods have been developed, combining the use of Type I collagen, hyalorunan-based scaffolds or Type I/II collagen membrane, but no significant clinical differences have been observed between the 1st and 2nd generation ACI methods.

All of the above therapeutic approaches face common problems, such as leakage of transplanted cells, potential periosteum hypertrophy, loss of chondrogenic phenotype of the cells and need to sacrifice healthy cartilage. However, their major disadvantage is the limited number of autologous cells available for transplantation. Therefore, finding an alternative, potentially unlimited source of cells available for transplantations is one of the major goals of the regenerative approach in OA, as well as in other degenerative diseases.

Potentially, several types of cells can be used for this purpose: human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), adult stem cells from various tissues and in situ chondrogenic progenitor cells (CPCs).

hESCs and iPSCs possess unlimited proliferative capacity and can provide an infinite supply of pluripotent cells. Their chondrogenic potential was successfully demonstrated both in vitro and in animal models, but transition to clinical use requires detailed investigation of their tumorogenic properties.

Recently, chondrogenic progenitor cells population (CPCs) has been discovered in articular cartilage of late-stage OA patients.  These cells are able to differentiate into the chondrogenic lineage and can perhaps be more easily induced as they are already present in the relevant physiological context in contrast to the stem cells from a different tissue. However, the ability of CPCs to produce extracellular matrix that supports cartilage regeneration, and importantly, the duration of time CPCs can maintain their chondrogenic potential have to be determined. 

Mesenchymal Stem Cells (MSCs) are multipotent stem cells with a strong potential to differentiate into various types of mesenchyme-derived cells. MSCs can be obtained from various tissues in the body, although the number of derived cells varies significantly from one source to another. Comparative analysis of MSCs revealed significant differences in their ability to differentiate into chondrogenic lineages depending on the origin of derivation, where the most potent are synovium-derived MSCs, followed by bone marrow-derived cells. Various studies demonstrated that MSCs obtained from patients with OA have equal chondrogenic potential to this of the healthy donors. Furthermore, MSCs possess anti-inflammatory properties which can be beneficial against progressive inflammation associated with OA progression.

At least three types of MSCs have been pre-clinically and clinically tested for treatment of cartilage defects: bone marrow-derived MSCs, adipose-derived MSCs (ADMSCs) and synovial-derived MSCs.

Bone marrow-derived MSCs comprise the most frequently used source of MSCs, while the obtained cells can be further used directly for injection (BMC) or expanded in culture (BMSCs). Direct use of concentrated bone marrow-derived cells fraction (BMC) for transplantation in OA has been evaluated. However, the number of MSCs in the bone marrow aspirate is relatively low, therefore following aspiration the cells can be expanded in culture. This expansion step provides several clear benefits, such as the possibility of banking and long-term use, and the remarkable added value of the ability to manipulate BMSCs to increase the cell number or to govern the cells to a specific lineage.

The efficiency of BMCs and BMSCs, injected or surgically implanted in combination with biological components (collagen powder or gel, platelet rich plasma) or scaffolds (hyaluronic acid membrane, hydroxyapatite ceramic), in OA cartilage repair was tested in numerous pre-clinical and clinical studies. All studies demonstrated promising positive results, including improved clinical, histological and arthroscopic scores, significant cartilage regeneration, in some cases, complete defect healing. ChondrocellTM is an example of autologous bone marrow-derived mesenchymal stem cells used for treatment of osteoarthritis. The therapy has reached advanced 2nd phase in clinical trials and the treated patients benefit from pain relief and greater mobility.

Adipose-derived MSCs (ADMSCs) represent an additional population of mesenchymal stem cells whose chondrogenic potential has been explored. Some studies demonstrate that the frequency of MSCs in the isolated adipose fraction is higher than in bone marrow, making ADMSCs potentially preferable. To date, the ability of ADMSCs to regenerate defective cartilage has been primarily evaluated in animal models and has demonstrated a lower chondrogenic potential compared to bone marrow-derived MSCs. Currently, RNL-JointStem®, autologous adipose-derived mesenchymal stem cells, are tested in Phase 1/2  to evaluate the efficacy and safety in patients with degenerative arthritis.

Synovial-derived MSCs possess the greatest chondrogenic potential among all the MSC types tested in pre-clinical models. Complete cartilage repair was achieved when synovial-derived MSCs were transplanted either in combination with collagen or extracellular matrix obtained from the in vitro cell culture. Still, further detailed research will be required to evaluate their clinical potential.

All the pre-clinical and clinical results described demonstrate the attractiveness of MSCs in cell therapy for osteoarthritis. Yet, considering the complexity of osteoarthritis pathophysiology, cartilage preservation and restoration is still the main objective in OA management. The ultimate goal is to prevent OA progression to end-stage osteoarthritis and as a consequence, to avoid the need for total joint replacement, which typically fail to address the needs of younger and physically active patients. The present challenge is to combine the latest developments in tissue engineering, novel scaffolds and biomaterial fabrication with stem cells of high chondrogenic potential to produce a functional tissue capable of repairing major cartilage defects.