Biomedical Engineering Reference
In-Depth Information
removal of the bone matrix, and is a morphologic characteristic of an osteoclast
that actively resorbs the bone. The mineral portion of the matrix (hydroxyapatite)
includes calcium and phosphate ions. These ions are absorbed into small vesicles,
which move across the cell and eventually are released into the extracellular fluid,
thus increasing the levels of the ions in the blood.
Osteoclasts possess an efficient pathway for dissolving crystalline hydroxyapatite
and degrading organic bone matrix rich in collagen fibers. When initiating bone
resorption, osteoclasts become polarized, and three distinct membrane domains
appear: a ruffled border, a sealing zone, and a functional secretory domain.
Simultaneously, the cytoskeleton undergoes extensive reorganization. During this
process, the actin cytoskeleton forms an attachment ring at the sealing zone, the
membrane domain that anchors the resorbing cell to the bone matrix.
The ruffled border appears inside the sealing zone, and has several characteris-
tics of late endosomal membrane. Extensive vesicle transport to the ruffled border
delivers hydrochloric acid and proteases to an area between the ruffled border and
thebonesurfacecalledthe
resorption lacuna
. In this extracellular compartment,
crystalline hydroxyapatite is dissolved by acid, and a mixture of proteases degrades
the organic matrix. The degradation products of collagen and other matrix com-
ponents are endocytosed, transported through the cell, and exocytosed through
a secretory domain. This transcytotic route allows osteoclasts to remove large
amounts of matrix-degradation products without losing their attachment to the
underlying bone. It also facilitates further processing of the degradation products
intracellularly during the passage through the cell.
1.3.5
Cellular Image - OPG/RANK/RANKL Signaling System
Recently, it has become clear that osteoclasts are not simply trench digging
cells, but that they have important regulatory functions as immunomodulators in
pathologic states and that they may also regulate osteoblast function. Proper growth
and functioning of osteoclasts is controlled by a pathway in which three factors,
osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB (RANK), and
receptor activator for nuclear factor-kappa B ligand (RANKL), play the main role.
RANK and its ligand (RANKL) are important members of the tumor necrosis factor
receptor (TNFR) and tumor necrosis factor (TNF) superfamilies, respectively.
OPG is secreted by osteoblasts and osteogenic stromal stem cells and protects
the skeleton from excessive bone resorption by binding to RANKL and preventing
it from interacting with RANK. The RANKL/OPG ratio in bone marrow is an
important determinant of bone mass in normal and disease states. RANKL/RANK
signaling also regulates the lymph node formation and mammary gland lactational
hyperplasia in mice, and OPG protects large arteries from medial calcification.
OPG and RANKL proteins are mainly located in Golgi areas.
RANK, also known as tumor necrosis factor-related activation-induced cytokine
(TRANCE) receptor, is a type I membrane protein, which is expressed on the surface
of osteoclasts and is involved in their activation upon ligand binding. RANK is also
