Beyond Cartilage Repair: The Role of the Osteochondral Unit in Joint Health and Disease

Abstract

Once believed to be limited to articular cartilage, osteoarthritis is now considered to be an organ disease of the “whole joint.” Damage to the articular surface can lead to, be caused by, or occur in parallel with, damage to other tissues in the joint. The relationship between cartilage and the underlying subchondral bone has particular importance when assessing joint health and determining treatment strategies. The articular cartilage is anchored to the subchondral bone through an interface of calcified cartilage, which as a whole makes up the osteochondral unit. This unit functions primarily by transferring load-bearing weight over the joint to allow for normal joint articulation and movement. Unfortunately, irreversible damage and degeneration of the osteochondral unit can severely limit joint function. Our understanding of joint pain, the primary complaint of patients, is poorly understood and past efforts toward structural cartilage restoration have often not been associated with a reduction in pain. Continued research focusing on the contribution of subchondral bone and restoration of the entire osteochondral unit are therefore needed, with the hope that this will lead to curative, and not merely palliative, treatment options. The purpose of this narrative review is to investigate the role of the osteochondral unit in joint health and disease. Topics of discussion include the crosstalk between cartilage and bone, the efficacy of diagnostic procedures, the origins of joint pain, current and emerging treatment paradigms, and suitable preclinical animal models for safety and efficacy assessment of novel osteochondral therapies. The goal of the review is to facilitate an appreciation of the important role played by the subchondral bone in joint pain and why the osteochondral unit as a whole should be considered in many cases of joint restoration strategies. Impact Statement In this comprehensive review, we are providing a holistic overview of osteochondral tissue development, disease, pain localization, as well as structural evaluation and current repair strategies. This review is intended to serve as a broad introduction to this multidisciplinary research area. It is a thorough examination of the biological aspects of the osteochondral unit from a tissue engineering perspective, highlighting the importance of the subchondral bone in chondral and osteochondral lesion repair and pain relief.

Macrophage: A Potential Target on Cartilage Regeneration

“…After initial stimulation, macrophages acquire a phenotype, ranging from pro-inflammatory (M1) to anti-inflammatory (M2) (36). In the joint, CD14 and CD163 are associated to proinflammatory and anti-inflammatory phenotypes, respectively (28).…”

“…M1 macrophages can be induced by interferon-g (IFN-g) and lipopolysaccharide (LPS) increasing CD80 expression (41). Lepage et al also stated that monocytes subjected to TNF-a can polarize to M1 phenotype (36). Once in contact with these stimuli, transcription factors, such as IRF5 activates transcription of genes encoding IL-12, IL-23 and represses IL-10 (42).…”

“…M1 stimulation also leads to nitric oxide (NO) production and cell surface expression of the co-stimulatory molecules CD86, CD80, and MHC, which are required for T cell activation (43). In general, M1 macrophages have high microbicidal activity and secrete large amounts of pro-inflammatory cytokines ( Table 1) (36,44).…”

“…These cells present an antiinflammatory function producing, IL-10, IL-1RA, chemokine (CeC motif) ligand 18 (CCL18), and TGF-b (31,46) as well as pro-chondrogenic factors: TGF-b1, TGF-b2, TGF-b3, insulinlike growth factor 1 (IGF1), and 2 (IGF2) (33) ( Table 1). The IL-10-induced subtype M2c plays a role in tissue remodeling (36). Some of the known M2-related genes are ARG-1, resistin like alpha (FIZZ1), mannose receptor, C type 1 (MRC), human macrophage galactose-type C-type lectin (CLEC10A) (47).…”

“…Synovial M1 macrophages were also shown to up regulate the production of proteolytic enzymes, such as matrix metalloproteinase (MMP)-1, MMP3, MMP13, MMP9 aggrecanases (ADAMTS), and cyclooxygenase-2, which contribute to articular degeneration (8,30,31). It was demonstrated that synovial macrophages and monocytederived pro-inflammatory macrophages negatively affected chondrogenesis of MSCs (36). M2 macrophages have a major role in tissue repair (44), and the shift from M0 toward M2 macrophages in the lesion might contribute to repair the damaged articular cartilage.…”