ABSTRACT

During embryonic development, bone formation begins with the condensation of mesenchymal stem cells. In a number of places in the body, such as the flat bones of the skull, bone formation is driven by a process called intramembranous ossification, where mesenchymal stem cells differentiate directly into bone-forming osteoblasts. In most other places, however, bones are formed by a different process known as endochondral ossification (Figure 16.1; for review, see Kronenberg [1]). In this process, mesenchymal stem cells first differentiate into chondrocytes. These chondrocytes secrete cartilage matrix composed mainly of type II collagen. Proliferation of chondrocytes leads to an overall expansion of this cartilage tissue and, in the center of the cartilage, cells stop dividing and start enlarging to become type X collagen-producing hypertrophic chondrocytes. These hypertrophic chondrocytes drive cartilage matrix mineralization, and eventually undergo apoptosis, leaving a cartilage matrix scaffold for the invasion of blood vessels and osteoblasts to lay down bone matrix in the center of the cartilage, known as the primary ossification center. As chondrocytes continue to proliferate, undergo hypertrophy, and are then invaded by osteoblasts, the long bones continue to lengthen and ossify in the center, resulting in longitudinal bone growth and an overall increase in body size and height. Gradually, as bones continue to grow in length, endochondral ossification becomes increasingly restricted to the cartilaginous structure found near the two opposite ends of long bones known as the growth plate. Within each growth plate, chondrocytes are arranged into three histologically distinct zones called resting, proliferative, and hypertrophic zones. Closest to the epiphysis, round and slowly dividing resting chondrocytes serve as precursor cells capable of self-renewing and giving rise to new clones of proliferative chondrocytes. In the proliferative zones, cells are arranged in columns parallel to the long axis of the bone and, within each column, chondrocytes undergo rapid proliferation, pushing themselves gradually toward the center of the bone, where they undergo the same process of hypertrophy and apoptosis. In late adolescence, as adult height is gradually attained, the growth plate continues to narrow, until growth potential is depleted, the epiphyseal fuses, and growth in height stops.