Unfolding the Mystery Behind the Onset of Chondrocyte Hypertrophy during Chondrogenesis: Toward Designing Advanced Permanent Cartilage‐mimetic Biomaterials

Abstract

Successful recapitulation of the anatomical microarchitecture and biomechanics of the native articular cartilage under in vitro culture conditions is still an elusive topic of research. The major roadblock lies in maintaining the stable chondrogenic phenotype in vivo or under long‐term in vitro conditions. Tissue engineers worldwide has coined this aberrant loss of permanent cartilage characteristics to transient cartilage form as “chondrocyte hypertrophy”. Although the following has been validated through the expression of a few known markers but very little is understood regarding the molecular mechanism that dwells underneath. This review summarizes the precise aetiology behind the development and progression of the hypertrophic phenotype in chondrocytes under in vitro chondrogenic conditions. Based on the current literature survey, it is deciphered that the type of cell utilized (chondrocytes or stem cells), the chondrogenic culture conditions (growth factors/biochemical mediators) and the culture microenvironment (oxygen tension, mechanical loading) during chondrogenesis have a direct correlation with the dysregulated activity of the chondrogenic signaling pathways corroborating the onset of hypertrophic maturation of chondrocytes. Furthermore, it is critically analyzed whether to completely inhibit these hypertrophy‐inducing signaling pathways or apply a brake in terms of time‐dependent dose due to their functional duality role in chondrogenesis.

Assessing the advantages of 3D bioprinting and 3D spheroids in deciphering the osteoarthritis healing mechanism using human chondrocytes and polarized macrophages

“…Chondrocyte hypertrophy and ECM degradation are the major hallmark features in OA progression [68,69]. Cartilage hypertrophy is a long-debated paradigm in articular cartilage development that counteracts chondrocyte maturation [70].…”

“…Thus, our 3D bioprinted constructs with silk matrices supported the stable M2 plasticity superiorly over 3D spheroids. Moreover, the expression profile of all these macrophage polarization surface markers (CD-14, CD-36, and CD- 68) showing maximum expression at day 7 and declining on day 10 encourages the development of a proinflammatory microenvironment promoting cartilage degradation during the early culture periods. This hypothesis can be further justified with the enhanced expressions of chondrocyte hypertrophy and matrix degradation markers COL-I, COL-X, MMP-1 and MMP-13 at the early time points that sublimed at day 10.…”

Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis

“…The superficial layer is disorganized, with focal matrix condensations, erosion and frequent matrix fibril ruptures. A characteristic glucosaminoglycan depletion can be seen in the deeper layers, which can be detected by safranin O staining [59]. In healthy cartilage, chondrocytes are homogeneously distributed, flattened in the superficial layer but round in the deep region.…”

“…Hypertrophy-like changes characterize both human and experimental OA, but do not involve all cells of the cartilage in a synchronized manner [58]. It has been proposed that hypertrophic differentiation of healthy articular chondrocytes occurs, at least in part, as a result of water entry through aquaporin channels [59]. The cells show increased organelle synthesis [57], and soluble compounds, and also the organic, stable microenvironment, interact with the differentiation process.…”

“…In contrast, osteoarthritic cartilage shows aggregated islands of chondrocytes of variable shape with the loss of characteristic organization and polarity. Experience gained in bioengineering experiments has shown that it is difficult to obtain a stable articular cartilage construct because of the shift to the so-called transient phenotype and hypertrophy instead of a stable permanent structure [59]. In the course of mesenchymal stem cell differentiation, several groups of signaling molecules dominate; BMP2,4,6, Indian hedgehog (IHH), parathormone-related peptide (PTHrP) signaling and the presence of angiogenic VEGF and pro-inflammatory IL-1β reflect commitment to the transient phenotype [59].…”