Regulation of chondrogenesis and chondrocyte differentiation by stress

Abstract

Chondrogenesis and endochondral ossification are the cartilage differentiation processes that lead to skeletal formation and growth in the developing vertebrate as well as skeletal repair in the adult. The exquisite regulation of these processes, both in normal development and in pathologic situations, is impacted by a number of different types of stress. These include normal stressors such as mechanical loading and hypoxia as well pathologic stressors such as injury and/or inflammation and environmental toxins. This article provides an overview of the processes of chondrogenesis and endochondral ossification and their control at the molecular level. A summary of the influence of the most well-understood normal and pathologic stressors on the differentiation program is also presented. Introduction to cartilageCartilage is a connective tissue that is comprised primarily of matrix (mainly collagens and proteoglycans) containing relatively sparse populations of chondrocytes, which perform matrix-generation and maintenance functions. During the development and growth of vertebrates, chondrogenesis is the dynamic cellular process that leads to the establishment of various types of cartilage, including hyaline, fibrous, and elastic cartilage. Hyaline cartilage is found in craniofacial structures, the trachea and bronchial tubes, the articular surfaces of diarthrodial joints, and the growth plate (GP) of long bones. GPs are responsible for driving the process of limb lengthening and bone growth during development pre- and postnatally. This type of bone growth involves the process of endochondral ossification (otherwise known as bone formation). The type of cartilage that is most prominent and most susceptible to both normal and pathologic forms of stress is the hyaline cartilage of the limb and trunk skeleton, which originates from the differentiation of condensed mesenchymal cells into clusters of cartilage cells known as chondrocytes. These cartilage anlagen preform the skeleton and provide a framework for endochondral bone development, a process that involves chondrocyte maturation and matrix mineralization in the GPs. The cells of each skeletal element proceed through a multi-step differentiation process generating both the mature GP cartilage, which controls skeletal growth during early and adolescent development, and the permanent articular cartilage (AC) found at the joint surface of all long bones.The processes of chondrogenesis and endochondral bone formation are not restricted to the developing skeletal system. In fact, following stress-related injuries, such as fractures of endochondral bone, the developmental programs of chondrogenesis and chondrocyte proliferation, maturation, hypertrophy, and terminal differentiation are reinitiated at the site of injury. Additionally, stress-related cartilage diseases such as osteoarthritis (OA) also have marked effects on the differentiation and maintenance of AC during adult life. This is why much attention has been paid to studying the cellular and molecular mechanism...

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