Abstract
Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have catastrophic results, as exemplified by several chondrodystrophies which are frequently accompanied by early onset osteoarthritis. Understanding the mechanisms that underlie chondrocyte apoptosis during endochondral ossification in the growth plate has the potential to impact the development of therapeutic applications for chondrodystrophies and associated early onset osteoarthritis. In recent years, several chondrodysplasias and collagenopathies have been recognized as protein-folding diseases that lead to endoplasmic reticulum stress, endoplasmic reticulum associated degradation, and the unfolded protein response. Under conditions of prolonged endoplasmic reticulum stress in which the protein folding load outweighs the folding capacity of the endoplasmic reticulum, cellular dysfunction and death often occur. However, unfolded protein response (UPR) signaling is also required for the normal maturation of chondrocytes and osteoblasts. Understanding how UPR signaling may contribute to cartilage pathophysiology is an essential step toward therapeutic modulation of skeletal disorders that lead to osteoarthritis.
Highlights
Long bones in the vertebrate body develop through the process of endochondral ossification
The physical properties of cartilage and bone can be attributed to the array of structural extracellular matrix (ECM) proteins secreted by both chondrocytes and osteoblasts
Compared to WT mice, the receptor for AGEs (RAGE)-knockout mice displayed an attenuated response to the surgery, as quantified by the OA biomarkers matrix metalloproteinase-13 (MMP-13), high temperature requirement protease A-1 (HtrA-1), and discoidin domain receptor-2 (Ddr-2) [23]. These findings suggest that advanced glycation end-products (AGEs)/RAGE signaling may contribute to OA in both early and later stages of life, rendering AGE/RAGE signaling a potential contributor to precocious OA
Summary
Long bones in the vertebrate body develop through the process of endochondral ossification. This process begins with the condensation of mesenchymal stem cells and the differentiation of these cells into chondrocytes. The physical properties of cartilage and bone can be attributed to the array of structural extracellular matrix (ECM) proteins secreted by both chondrocytes and osteoblasts. The collagens are structural, extracellular matrix (ECM) proteins that fulfill differing roles throughout the course of chondrogenesis. Recent perspectives have revealed that collagen misfolding has consequences for the extracellular microenvironment, and for the intracellular homeostasis of chondrocytes and osteoblasts. Unlike many of the cell types affected in such diseases, chondrocytes and osteoblasts undergo physiological UPR signaling in the course of normal maturation. UPR signaling has dually essential and detrimental roles in the bone development of individuals with congenital collagenopathies and chondrodysplasias
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