Wednesday 29 October 2003
Information regarding the molecular regulation of osteoclast formation in humans is limited. In mice, a number of transcription factors, including PU.1 and Fos, are essential for developing an osteoclast phenotype.
The cytokines and growth factors crucial for osteoclast differentiation and maturation in humans include interleukin IL1, IL3, IL6, IL11, tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage colony-stimulating factor (M-CSF).
This paracrine system is essential to bone metabolism, and its mediators include the molecules RANK (Receptor Activator for Nuclear factor κB), RANK ligand (RANKL), and osteoprotegerin (OPG).
RANK is a member of the TNF family of receptors expressed mainly on cells of macrophage/monocytic lineage such as preosteoclasts. When this receptor binds its specific ligand (RANKL) through cell-to-cell contact, osteoclastogenesis is initiated.
RANKL is produced by and expressed on the cell membranes of osteoblasts and marrow stromal cells; its major role in bone metabolism is stimulation of osteoclast formation, fusion, differentiation, activation, and survival.
The actions of RANKL can be blocked by another member of the TNF family of receptors, osteoprotegrin (OPG), which is a soluble protein produced by a number of tissues, including bone, hematopoietic marrow cells, and immune cells.
OPG inhibits osteoclastogenesis by acting as a decoy receptor that binds to RANKL, thus preventing the interaction of RANK with RANKL.
Therefore, interplay between bone cells and these molecules permits osteoblasts and stromal cells to control osteoclast development.
This ensures the tight coupling of bone formation and resorption vital to the success of the skeletal system, and provides a mechanism for a wide variety of biologic mediators (hormones, cytokines, growth factors) to influence the homeostasis of bone tissue.
Mature multinucleated osteoclasts (containing 6 to 12 nuclei) form from fusion of circulating mononuclear precursors and have a limited life span (approximately 2 weeks). They are intimately related to the bone surface, where their activity is initiated by binding to matrix adhesion proteins. The scalloped resorption pits they produce, and frequently reside in, are known as Howship lacunae.
The portion of the osteoclast cell membrane overlying the resorption surface is modified by numerous villous extensions, known as the ruffled border, which serve to increase the membrane surface area.
The plasmalemma bordering this region is specialized and forms a seal with the underlying bone, preventing leakage of digestion products.
This self-contained extracellular space is analogous to a secondary lysosome, and the osteoclast acidifies it with a hydrogen pump system that solubilizes the mineral. The osteoclast also releases into this space a multitude of enzymes that help disassemble the matrix proteins into amino acids and liberate and activate growth factors, cytokines, and enzymes (such as collagenase), which have been previously deposited and bound to the matrix by osteoblasts. Thus, as bone is broken down to its elemental units, substances are released into the microenvironment that initiate its renewal.
The proteins of bone include type 1 collagen and a family of noncollagenous proteins that are derived mainly from osteoblasts.
Type 1 collagen forms the backbone of matrix and accounts for 90% of the weight of the organic component. Osteoblasts deposit collagen either in a random weave known as woven bone or in an orderly layered manner designated lamellar bone.
Normally, woven bone is seen in the fetal skeleton and is formed at growth plates. Its advantages are that it is produced quickly and resists forces equally from all directions.
The presence of woven bone in the adult is always indicative of a pathologic state; however, it is not diagnostic of a particular disease. For instance, in circumstances requiring rapid reparative stability, such as a fracture, woven bone is produced. It is also formed around sites of infection and composes the matrix of bone-forming tumors. Lamellar bone, which gradually replaces woven bone during growth, is deposited much more slowly and is stronger than woven bone. There are four different types of lamellar bone.
Three are present only in the cortex-circumferential, concentric, and interstitial (Fig. 26-6). The fourth type, trabecular lamellae, composes the bone trabeculae in which the lamellae are oriented parallel to the long axis of the trabeculum.
The noncollagenous proteins of bone are bound to the matrix and grouped according to their function as adhesion proteins, calcium-binding proteins, mineralization proteins, enzymes, cytokines, and growth factors.
Of these, only osteocalcin is unique to bone. It is used as a sensitive and specific serum marker for osteoblast activity. Cytokines and growth factors control bone cell proliferation, maturation, and metabolism.
They serve an important messenger function in translating mechanical and metabolic signals into local bone cell activity and eventual skeletal adaptation. In this fashion the skeleton is uniquely able to change its structure in response to new physical forces; witness the repositioning of teeth by the forces of braces.
Pathology of osteoclasts
Teitelbaum SL, Ross FP. Genetic regulation of osteoclast development and function. Nat Rev Genet. 2003 Aug;4(8):638-49. PMID: 12897775