Bone Homeostasis

Appearances aside, bone is a dynamic organ undergoing constant remodeling and adaptation in response to mechanical, systemic, and local factors. This process involves the closely coupled destruction of existing bone by osteoclasts followed by deposition of new bone by osteoblasts. If either of these processes—destruction or formation—is interrupted, pathology is observed. Bone multicellular units (BMUs) composed of osteoblasts, osteoclasts, and osteocytes are responsible for maintaining bone homeostasis and for repair and regeneration following injury.

Osteoblasts and Osteocytes

Osteoblasts are derived from mesenchymal tissue along a tightly regulated pathway. Mesenchymal cells can form connective tissue fibroblasts, adipocytes, and bone. Differentiation of mesenchymal cell into osteoblasts occurs along a pathway involving regulation by autocrine, paracrine, and endocrine factors. Endocrine factors including parathyroid hormone, growth hormone, and insulin-like growth factor stimulate proliferation and in certain instances differentiation for pre-osteoblastic cells.

Critically, RUNX2, a nuclear transcription factor, must be expressed for a mesenchymal cell to differentiate along an osteoblastic lineage. The mechanisms by which expression of RUNX2 lead eventually to an osteoblast phenotype are beyond the scope of this chapter. However, it should be noted that bone morphogenetic proteins (BMPs) are critical for the induction of RUNX2 expression. BMPs are a member of the transforming growth factor family of proteins, and to date 30 have been identified. BMPs are present in bone and become soluble following demineralization. At that point they are able to exert inductive effects on differentiating cells in the osteoblast lineage. Thus, bone formation, at least in adulthood, is critically dependent on bone destruction occurring first. Several existing and emerging therapeutic approaches in bone grafting are intended to introduce autogenous BMPs, allogenic BMPs, or more recently, recombinant BMPs to a surgical site.

Once fully differentiated, osteoblasts synthesize an extracellular matrix principally composed of type 1 collagen but also containing other molecules. This matrix eventually becomes calcified and the osteoblasts are encased within the mineralized tissue. At that point the osteoblast is called an osteocyte. Osteocytes communicate with one another via dendritic processes, and the function of viable osteocytes with bone appears to be one of mechanosensation. Thus, bone that is not being mechanically stimulated tends to atrophy, while the converse is true of bone stimulated by exercise.

Osteoclasts

Osteoclasts are multinucleated cells of hematopoietic lineage, specifically of the monocyte/macrophage lineage. Differentiation of monocytes to osteoclasts requires physical contact with osteoblasts or stromal cells. Osteoblasts express receptor activator of nuclear factor κβ-ligand (RANKL) on their membrane surface, which binds to the RANK receptor on osteoclast precursor macrophages and induces them to differentiate and eventually fuse into multinuclear cells, called osteoclasts. Osteoblasts also produce monocyte colony stimulating factor (M-CSF), which stimulates proliferation of osteoclast precursors. Whereas RANKL binds to RANK and stimulates osteoclastogenesis, the soluble molecule and decoy receptor osteoprotegrin (OPG) competitively binds RANKL and inhibits osteoclastogenesis. The relative proportions of RANKL and OPG have been termed the RANKL/OPG axis and seem to be instrumental in inflammation-dependent bone loss. This is especially significant for maintaining long-term stability of bone levels around the osseointegrated implant. This will be discussed later in this chapter.

BMUs

Osteoblasts, osteoclasts, and osteocytes are organized into BMUs. These units are organized as cutting cones, which are led by osteoclasts that resorb bone and are trailed by osteoblasts that lay down new bone and eventually become osteocytes. BMUs have a limited life span and new units are continually formed to replace old, inactive ones. In good health, about 3–5% of an individual’s skeleton is being replaced at any given time and there is a relative homeostasis between bone formation and resorption.