Bone may seem to be stable and unchanging, but in fact, bone is constantly being remodeled. Bone remodeling is triggered by a need for calcium in the extracellular fluid, but it also occurs in response to mechanical stresses on the bone tissue.
To understand bone remodeling, and the factors that lead to pathological problems with bone, you need to know about three cell types found in bone.
Osteoblasts are bone-forming cells. They are connective tissue cells found at the surface of bone. They can be stimulated to proliferate and differentiate as osteocytes.
Osteocytes are bone cells. Osteocytes manufacture type I collagen and other substances that make up the bone extracellular matrix. Osteocytes will be found enclosed in bone.
Osteoclasts are bone-resorbing cells ("-clast" means to break; osteoclasts break down bone). They are large, multinucleate cells that form through the fusion of precursor cells. Unlike osteoblasts, which are related to fibroblasts and other connective tissue cells, osteoclasts are descended from stem cells in the bone marrow that also give rise to monocytes (macrophages).
Bone resorption can be triggered by parathyroid hormone (PTH) in response to hypocalcemia. PTH stimulates the generation of new osteoclasts (osteoclastogenesis, see below). After osteoclasts form, the first step necessary for bone resorption to occur is that the mature osteoclast needs to tightly adhere to the bone, creating a specialized isolated compartment. Once the osteoclast adheres to the bone surface, the membrane adjacent to the bone differentiates as the ruffled membrane. The ruffled membrane contains proteins that acidify the compartment adjacent to the bone. The acid dissolves the minerals in the bone; subsequently, proteases break down type I collagen and other proteins. Bone resorption ends when the osteoclast dies by apoptosis.
PTH stimulates bone resorption by osteoclasts, but it does so
indirectly. Receptors for PTH are located on osteoblasts,
which then signal to bone marrow-derived osteoclast precursors to
stimulate their fusion, differentiation and activation. Osteoclast
precursors express a cell-surface receptor known as RANK
(RANK stands for Receptor Activator of Nuclear
factor-Kappa B). Osteoblasts express RANKL (RANK Ligand)
on the extracellular surface of their plasma membrane.
When they are stimulated by PTH, osteoblasts up-regulate expression of RANKL, which binds to RANK, activating signaling pathways that promote osteoclast differentiation and survival. Osteoblasts also express a secreted factor called osteoprotegerin. As its name implies, osteoprotegerin "protects bone" by preventing bone resorption. Osteoprotegerin works as a decoy receptor for RANKL: it binds RANKL and therefore prevents binding to RANK and stimulation of osteoclastogenesis. The ratio of osteoprotegerin:RANKL produced by osteoblasts will determine the extent of bone resorption.
A new drug has been developed for the treatment of osteoporosis
that targets the interaction between RANK and RANKL. Denosumab is monoclonal
antibody that binds to RANKL; thus it mimics the effect of
osteoprotegerin. Denosumab (marketed as Prolia®) was approved for
the treatment of osteoporosis in June 2010. Refer to the
page on Osteoporosis.