The skeleton, like every organ, has specific developmental and functional characteristics that define its identity in biologic and pathologic terms. Skeleton is composed of multiple elements of various shapes and origins spread throughout the body. Most of these skeletal elements are formed by two different tissues, cartilage and bone, and each of these two tissues has its own specific cell types: the chondrocyte in cartilage, and the osteoblast and osteoclast in bone. Finally, each of these cell types has its own differentiation pathway, physiological functions, and therefore pathological conditions. The complexity of this organ in terms of developmental biology, physiology, and pathology, along with the multitude of important conceptual advances in our understanding of skeletal biology, are such that it has become impossible to present in a short review an up-to-date summary of both cartilage and bone biology. Thus, this review will concentrate only on bone biology beyond embryonic patterning. The entire bone field is dominated by the impact of degenerative diseases, such as osteoporosis. This mere fact does influence the research in bone biology and will influence the topics presented in this review. It is no surprise that, like for most other organogenesis processes, human and mouse genetic studies have been a major driving force in redefining bone biology. Genetic studies have opened new areas of research, elucidated at the molecular level some known phenomena, and sometimes challenged untested textbook assumptions, thus transforming the field profoundly. In mammals, bone development is a late embryonic event as it is the last event of skeleton development. Once the mesenchymal condensations prefiguring each future skeletal element have formed, between 10.5 and 12.5 days postcoitum (dpc) in mouse, they can evolve along two different paths. In some skeletal elements, prefiguring part of the skull and the clavicles, the cells of the mesenchymal condensations differentiate directly into osteoblasts that appear at 15.5 dpc of mouse development (Hall and Miyake 1992; Huang et al. 1997). This process is called intramembranous ossification. For the rest of the future skeleton, cells of the mesenchymal condensations differentiate into chondrocytes forming the “cartilage anlagen” of the future bones. In the periphery of the anlage, cells from the perichondrium differentiate into osteoblasts, while the periphery of the anlage become hypertrophic. Eventually, the matrix surrounding these hypertrophic chondrocytes calcifies and blood vessel invasion of the calcified cartilage brings in osteoblasts∼ 14.5–15.5 dpc (Horton 1993; Erlebacher et al. 1995). Once a bone matrix is deposited the bone marrow forms and the first osteoclasts appear (Hofstetter et al. 1995). Thus, sequential appearance of a cartilage anlage, calcified cartilage, and then bona fide bone characterizes the endochondral ossification. Regardless of the mode of ossification, osteoblast differentiation precedes osteoclast differentiation.

One peculiar characteristic of bone resides in its physiology. Bone is the only organ that contains a cell type, the osteoclast, whose only function is to constantly destroy the organ hosting it. This destruction, or resorption, of bone occurs throughout life and in healthy individuals is counterbalanced by de novo bone formation in a process called bone remodeling (Frost 1969). It is through bone remodeling that bone mass is maintained at a constant level between the end of puberty and gonadal failure, and bone remodeling is the process affected during osteoporosis, a disease characterized at the cellular level by a relative increase of bone resorption over bone …