in an amorphous gel-like material. It is essential for growth both before and after birth. In the embryo, the axial and the appendicular skeleton are formed first as cartilage and are replaced by bone. Apart from the capability to undergo rapid growth, cartilage maintains a substantial degree of stiffness, which provides support to the skeleton and holds bones together. It functions to reduce friction and has a cushioning effect between joints. Unlike other types of tissue, cartilage does not have a blood supply, which delays its healing ability. Various disease states are associated with cartilage pathology. Ongoing stem cell research at the Johns Hopkins Medicine Joint Repair Department is using MSCs in a key step toward creating minimally invasive procedures that may be used to repair injured cartilage tissues.
Osteoarthritis
Osteoarthritis (OA) is the most common form of arthritis. It is also called the degenerative joint disease and is one of the 10 most disabling conditions in the developed countries. Osteoarthritis shows a strong positive correlation with aging, with a presentation of bone pain in the elderly. Pathologically, it is an intrinsic disease of cartilage in which biochemical and metabolic alterations in individuals with genetic susceptibility result in its breakdown. Although the term osteoarthritis indicates an inflammatory disease, it is not the predominant feature.
Risk factors for OA include hormonal status, obesity, high bone mineral density, smoking, aging, trauma, joint shape, and usage (occupational or recreational). Twin studies and family studies also show a strong relation to genetics, proving that inheritance is a major factor, particularly in hand and generalized OA along with knee OA. More commonly, a symptomatic condition is experienced by women, except at the hip where men are equally affected.
A variety of mechanical, genetic, and metabolic insults may result in damage of the synovial joints and require repair. In most instances, osteoarthritis appears insidiously, as an aging phenomenon (primary or idiopathic). In these cases, the disease affects few joints but may be generalized. In a small number of cases, osteoarthritis may appear in younger individuals having a predisposing condition such as a previous injury, congenital deformity, or an underlying systemic disorder such as diabetes, hemochromatosis, or marked obesity. In these cases the condition is called secondary osteoarthritis and often involves several joints. Insult to any tissue of the joint (cartilage, bone, capsule, ligament, muscle) causes an impact on the others, resulting in a common phenotype affecting the whole joint.
Often the slow but efficient OA process compensates for the insults, resulting in a pain-free functioning joint. However, due to overwhelming function or poor repair response, it fails (joint failure). The consequential cartilage changes are at the center of the process: (1) there is enzymatic degradation of the major components aggrecan and collagen, (2) the chondrocytes increase their production of matrix components and divide to produce nests of metabolically active cells, and (3) the concentration of aggrecan molecules falls, with an increase in water concentration and swelling pressure of cartilage, further disrupting the type 3 collagen. Thus, the cartilage is vulnerable to load-bearing injury. Cartilage loss is focal and usually restricted to the maximum load-bearing part of the joint.
The extreme burden of OA is aggravated by the insufficiency of current therapies. Pharmacologic and surgical interventions have been used for early cases and when symptoms cannot be controlled with progression of the disease, respectively. Recently, adult mesenchymal stem (MSC) cells, having the ability to differentiate into cells of chondrogenic lineage, have emerged as a treatment with possible great potential. Various varieties of stem cells have shown to differentiate in the presence of appropriate growth stimuli along chondrogenesis pathways.
Stem cells have been isolated from bone marrow and other tissues of mesenchymal origin, such as adipose tissue, placenta, umbilical cord, and amnion. The renewing ability and differentiation potential into chondrocytes has already been documented. Also, the use of mesenchymal cells is not hindered by the availability of healthy cartilage or an intrinsic tendency of the cells to lose their phenotype during expansion. The need for cartilage biopsy is eliminated, thereby avoiding morbidity caused by damage to the donor-site articular surface.
The anti-inflammatory and immunosuppressive properties of stem cells from tissues like bone marrow ensure that cells reduce inflammation in the affected joint. It is hypothesized that the transplanted stem cells can initiate the repair process by differentiating into chondrocytes or by inducing proliferation of the remaining healthy chondroprogenitor cells into mature chondrocytes. In a study by Murphy and colleagues, stem cells isolated by bone marrow tissue were suspended in hyaluronan solution and injected intra-articularly in goats with induced OA. Regeneration of tissue was evident in animals receiving cells in the cartilage area. Similar studies have shown encouraging results and thus it is evident that mesenchymal stem cells embedded on biodegradable scaffold have the potential to be therapeutically effective for conditions such as osteoarthritis.
Genetic Abnormalities
Achondroplasia is the most common disease of the growth plate and is a major cause of dwarfism. It is caused by a mutation in the FGF receptor 3 (FGFR3) that causes constitutive activation of the gene and thereby suppresses growth. This dwarfing condition is an autosomal dominant disorder, which causes an abnormal proliferation and maturation of chondrocytes. Affected individuals have shortened proximal extremities, a trunk of normal length, and an enlarged head with bulging forehead and depression of the root of the nose. The primary defect in patients with achondroplasia is abnormal endochondral ossification. Tubular bones are short and broad, indicating normal periosteal growth. The iliac crest apophyses are normal, while the growth of the triradiate cartilage is abnormal. This gives rise to horizontal acetabular roofs. These patterns of defect help explain the clinical and radiographic characteristics of achondroplasia.
A similar condition, called hypochondroplasia is also a form of short-limbed dwarfism. Hypochrondroplasia interferes with the ossification process, affecting the conversion of cartilage into bone. This is significantly seen in the long bones of arms and legs, with the adult height for men ranging from 138 centimeters (cm) to 165 cm. The obvious clinical features include short stature, stocky build, rhizomelia, micromelia, generalized mild joint laxity, and macrocephaly. Recent studies are targeting stem cell transplantation to shorten the treatment period of patients with achondroplasia and hypochrondroplasia. Stem cells, once differentiated, could be used to correct similar conditions in which cartilage cells are deficient in number or function.
Relapsing Polychondritis
Relapsing polychondritis is a rare, multisystem, progressive inflammatory condition involving the cartilaginous structures. Predominantly, it affects the cartilage of ears, nose, and laryngotracheobronchial tree. The pathophysiology of polychondritis relates to autoimmunity. Although the specific etiology is unknown, there has been documented presence of circulating antibodies to cartilage-specific collagen types II, IX, and XI with patients with relapsing polychondritis and are present during different stages of the condition. Furthermore, the association of polychondritis with HLA-DR4 also suggests an autoimmune pathogenesis. High prevalence of several other autoimmune disorders has been linked to relapsing polychondritis. Many patients with this condition concurrently have other disorders such as rheumatoid arthritis, Sjögren syndrome, and systemic lupus erythematosus. Finally, relapsing polychondritis has been linked to internal paraneoplastic malignancies.
Apart from traditional treatment consisting of anti-inflammatory and immune suppressive steroids, current research is aiming to evaluate the effects of stems cells on specific autoimmune conditions. The Colorado Stem Cell Treatment Center has developed a specific SVF protocol for polychondritis that attempts to utilize the regenerative properties of SVF (which is rich in mesenchymal stem cells).
Tumors
Cartilage tumors account for the majority of primary bone
