Recent Insights into the Contribution of the Changing Hypertrophic Chondrocyte Phenotype in the Development and Progression of Osteoarthritis

Abstract

Osteoarthritis (OA) is an extremely prevalent age-related condition. The economic and societal burden due to the cost of symptomatic treatment, inability to work, joint replacement, and rehabilitation is huge and increasing. Currently, there are no effective medical therapies that delay or reverse the pathological manifestations of OA. Current treatment options are, without exception, focused on slowing down progression of the disease to postpone total joint replacement surgery for as long as possible and keeping the associated pain and joint immobility manageable. Alterations in the articular cartilage chondrocyte phenotype might be fundamental in the pathological mechanisms of OA development. In many ways, the changing chondrocyte phenotype in osteoarthritic cartilage resembles the process of endochondral ossification as seen, for instance, in developing growth plates. However, the relative contribution of endochondral ossification to the changing chondrocyte phenotype in the development and progression of OA remains poorly described. In this review, we will discuss the current knowledge regarding the cartilage endochondral phenotypic changes occurring during OA development and progression, as well as the molecular and environmental effectors driving these changes. Understanding how these molecular mechanisms determine the chondrocyte cell fate in OA will be essential in enabling cartilage regenerative approaches in future treatments of OA.

NF-κB Signaling Regulates Physiological and Pathological Chondrogenesis

“…Although these two pathways are known to be involved in the homeostasis of various cells and tissues, the homeostasis of articular chondrocytes is also maintained through the regulation of the proliferation, differentiation, and maturation of chondrocytes via these two pathways. Although in vitro experiments have suggested that TGF-β/BMP activates the classical NF-κB pathway [7,9,50], ligands that activate these two NF-κB activation pathways in vivo and their target genes, which regulate chondrocyte development, are still unknown. On the other hand, the production of inflammatory cytokines, such as TNFα or IL-1β, is increased in RA and OA, in which the joint is destroyed by chronic inflammation.…”

“…Inflammatory factors affect chondrocyte development. Chondrocytes in OA show increased expression of hypertrophic markers, such as type X collagen, alkaline phosphatase, and MMP13, indicating that OA-derived chondrocytes are mature and differentiated [13,49,50]. Although activation of the classical NF-κB pathway was observed in both RA and OA synovitis, the activation was higher in RA than OA [51].…”

“…Osteoarthritis (OA) is a degenerative disease in joints involving structural alternations in the articular cartilage, subchondral bone, and synovium, with pain and swelling caused by the imbalance between the repair and destruction of joint tissues such as knees, elbows, and shoulders [49,50]. Multifactorial conditions, such as failing joint biomechanics and immune and inflammatory responses, lead to the progression of OA [49,50]. Inflammatory factors affect chondrocyte development.…”

“…The expression MMPs and tissue inhibitors of MMPs (TIMPs) regulated by inflammatory cytokines degrade and preserve the extracellular matrix produced by chondrocytes, respectively, and they are involved in the onset and development of OA [49,50]. In normal joints, the proportion of TIMPs is greater than that of MMPs, but the amount of MMPs increases due to mechanical stimulation, substrate degradation products, and age-related glycation end products (AGEs) in OA [30,31].…”

Electrospun Polymers in Cartilage Engineering—State of Play

“…WNT signaling is a well-studied pathway for differentiation and hypertrophy (Ripmeester et al, 2018). WNTs establish a large family of cysteine-rich morphogens that have an essential role in cartilage, bone and joint development.…”