Osteoarthritis is a multifaceted, degenerative disease of the whole joint that causes loss of articular cartilage, subchondral bone sclerosis, synovitis, and myriad other symptoms and presentations, ultimately resulting in joint failure. It causes a substantial decrease in quality of life and poses an enormous financial burden.¹ With as much as 10% of the US population experiencing various forms of osteoarthritis, there is a clear and urgent need to develop treatment methods that lessen symptoms and improve disease outcomes. Osteoarthritis can affect any weight-bearing or non-weight-bearing joint in the body. The origins of disease are complex and include genetics/epigenetics, sex-related/hormonal differences, obesity/inflammation, gut microbiome changes, injury, aging/senescence, and other factors. Orthobiologics include platelet-rich plasma, hyaluronic acid, and stem cell-based therapies, as well as tissue engineering approaches. However, lack of standardization in methods, outcomes, study design, and the placebo effect make drawing conclusions about the efficacy of a given therapy difficult. It is important to review the fundamentals of joint biology, the complex etiologies of osteoarthritis, and various orthobiologics currently in use.

Articular cartilage is formed during embryogenesis through a sequential series of steps that include patterning of cell types and tissue structure at the sites of developing joints.² Chondrocytes residing in articular cartilage are mainly formed from interzone cells. Unlike chondrocytes in the epiphyseal plates, which undergo orchestrated differentiation leading to longitudinal bone growth and culminating in apoptosis, articular chondrocytes achieve a nonterminally hypertrophic state that supports their main cellular function: maintenance of extracellular matrix. Structurally, articular cartilage is maintained as four distinct cellular zones from the surface to the underlying bone: superficial, intermediate, radial, and calcified cartilage (Figure 1).
The superficial zone consists of one to two cell layers of flattened chondrocytes expressing proteoglycan 4 (Prg4) (also known as superficial zone protein or lubricin), Sox9, Col2a1(IIb), Agc1, Tnc, and low levels of cartilage intermediate layer protein (Cilp).² Chondrocytes of the intermediate zone are round and express many of the same molecules as the superficial zone except for Prg4, although they have higher levels of Cilp. Radial and calcified cartilage zone chondrocytes express markers of chondrocyte differentiation and hypertrophy, including Col10a1 (1).

The understanding of the behavior of articular chondrocytes has its foundations in broad literature studying these cells in vitro and in vivo. Articular chondrocytes removed from their matrix tend to dedifferentiate into type 1 collagen-expressing fibroblasts and lose their ability to express Col2a1 and other matrix components including proteoglycans.³ When cultured in suspension or in a three-dimensional (3D) matrix made of collagen, agar, or alginate, the cells will more accurately maintain their chondrocytic phenotype,³ emphasizing the importance of cell-matrix interactions in controlling gene expression. The predominant matrix protein in cartilage is type II collagen, which is composed of three individual Col2a1 chains forming a triple helix.² Like type I collagen, it is secreted as triple helical proprotein, which is cleaved extracellularly by proteinases.² The other major organic component of the matrix is proteoglycan, which includes a hyaluronic acid chain tethered to several proteins that are covalently bound to glycosaminoglycan side chains.² The major proteoglycan is aggrecan, which consists of a protein core associated with chondroitin sulfate and keratan sulfate side chains. These negatively charged polysaccharides serve to attract positively charged electrolytes to the proteoglycan superstructure, which serve to create the Donnan osmotic pressure that provides hydration and structural integrity of articular cartilage.⁴ In addition to type II collagen and aggrecan, articular chondrocytes produce a series of minor collagens that also contribute to tissue structure, including type VI, IX, X, and XI collagens. Type VI collagen is a pericellular matrix protein, whereas type IX is a collagen molecule with a proteoglycan moiety. Type IX collagen molecules coat the outer surface of type II collagen fibrils supporting interactions with matrix proteoglycans, an important
basis for interconnections between the collagen and proteoglycan matrix.

Because cartilage degeneration leading to its loss is a seminal feature of the osteoarthritis disease process, study of cartilage structure and articular chondrocyte function in this context has been a major focus of the work in the field. In general, chondrocyte maintenance of the matrix is a homeostatic process that persists through adulthood unless stress-related injury, inflammation (local or systemic), senescence, or genetic defects lead to loss of the signals required to maintain or inhibit inappropriate differentiation of chondrocytes (Figure 2). When pathways that decelerate or prevent chondrocyte hypertrophy are disrupted or impaired, progressive loss of mechanically appropriate articular cartilage matrix leads to degenerative disease.³ It is now understood that the inappropriate articular chondrocyte differentiation process of chondrocytes leading to cartilage loss needs to be viewed from a whole joint perspective (Figure 3, A), with subchondral bone, synovium, ligaments, tendons, and menisci (specifically in the knee joint) having a role to play in the loss of high-integrity cartilage. This holistic view of the joint sets the stage for the enumeration of the underpinnings of osteoarthritis disease initiation and progression and approaches for therapeutic intervention (Figure 3, B).

In much the same way that osteoarthritis is a whole-organ disease that involves interplay between various elements of the joint and whole body, there is no single etiologic mechanism of osteoarthritis. The osteoarthritis syndrome, which is characterized by the tissue phenotypes described earlier, is driven by numerous factors, including aging and cellular senescence; obesity and systemic inflammation; gut microbiome, genetic, and epigenetic factors; and sex hormones. Although the end point of the disease looks similar despite etiology, understanding etiology in a personalized medicine perspective will be critical in the development of targeted therapeutic approaches.