Bone
Remodelling
Introduction
The nature of bone. Bone is an essential rigid support for the
body, a means of effecting locomotion and a reservoir of ions such as calcium,
phosphate, magnesium and sodium. Bone is two-thirds mineral and the rest is
mainly type 1 collagen and water. Bone mineral is present mainly as crystalline
hydroxyapatite and the rest as amorphous calcium phosphate, which occurs in
higher amounts in actively forming, young bone.
Bone needs to be not only
rigid and strong but also light enough to allow muscle contractions. These
properties are con- ferred by the structure of bone, which in the case of
cortical tubular bones consists mainly of densely packed layers of mineralized collagen, and, in the case of the axial skeleton, of spongier
trabecular or cancellous bone. Defective cortical bone results in long bone
fracture, while defective trabecular bone results in vertebral fractures.
Cellular structure of bone
Bone matrix is laid down in
concentric layers called lamellae. The unit of structure in compact bone is the
osteon. In each osteon, lamellae
are arranged around
the central Haversian canal; the canal houses blood
vessels and nerves. The osteocytes are located in the lacunae, which are
connected by branching tubules called canaliculi. The canaliculi radiate out
from the lacunae to form an extensive network, connecting bone cells to each
other and to the blood supply.
Cell types in bone
The three main cell types in
bone are the osteoblast, osteocyte and osteoclast. The osteoblast is the
main bone-producing cell. It originates in the bone marrow and when mature
possesses receptors for, amongst other hormones, vitamin D and parathyroid
hormone (PTH). The differentiated, mature osteoblast migrates to the surface of
bone and lays down bone matrix in lamellae and induces mineralization. It
expresses alkaline phosphatase and a number of matrix proteins, including
osteocalcin and type 1 collagen. Osteocytes are osteoblasts entrapped in
cortical bone during remodelling; these develop processes which communicate
with other osteocytes and with capillaries, thus ensuring a supply of
nutrients.
Osteoclasts are large, multinucleated cells whose
function is the resorption of bone (Fig. 52a). They originate from haematopoietic mononuclear precursors of the monocyte/ macrophage lineage under the
influence of interleukin-1 (IL-1) and tumour necrosis factor (TNF) and
differentiate under the influence of a number of factors including: macrophage
colony-stimulating factor (M-CSF, also called CSF-1); GM-CSF (granulocyte
macrophage colony stimulating factor); TGF-b (transforming growth factor-b);
IL-6 and IL-11; vitamin D and PTH (Fig. 52b). There is evidence that
megakaryocyte cells express the receptor activator of NF-kB ligand (RANKL), a
member of the TNF ligand family, which is essential for the differentiation process.
RANKL attaches to RANK, a receptor on the cell surface of osteoclasts and
osteoclast precursors, to stimulate proliferation and differentiation of cells
to form the osteoclast. Osteoprotegerin (OPG) is a soluble decoy receptor
produced by osteoblasts, marrow stromal cells and other cells. It profoundly
modifies the effects of RANKL by inhibiting RANKL/RANK interaction. Osteoclasts
do not appear to have receptors for vitamin D or PTH. Osteoclasts resorb bone
by attaching themselves to bone matrix, breaking it down with catheptic
proteases and dissolving it in acid (Fig. 52a). After the osteoclast has
attached itself to bone, it seals off the underlying portion from the rest of
the bone and develops an invaginated border called the ‘ruffled border’, which
acts as a large lysosome, dissolving the surrounded portion of bone. Resorption
can be reduced by reducing the rate of osteoclast formation or by reducing
osteoclast activity.
Bone remodelling
Bone remodelling is the cycle
of bone resorption and new bone deposition. The cycle depends on systemic
hormone action for an adequate supply of calcium phosphate and on local hormone
action for communication between osteoblasts and osteoclasts. The balance
between mineral supply to the bone and bone resorption under the influence of
PTH is normally balanced by chemical signal coupling, which at present is poorly
understood. Bone remodelling is a continuous process, so that as bone is being
resorbed, new bone (osteoid) is being laid down by osteoblasts (Fig. 52c). In
cortical bone, remodelling occurs from within and four phases can be
identified: there is a resting phase, while osteoclasts become activated;
during the resorption phase, groups of osteoclasts cut tunnels through the
bone, followed by trailing osteoblasts; during the reversal phase, the
osteoclasts undergo apoptosis; and during the formation phase the osteoblasts
lay down new bone.
In cortical bone, osteoblasts
lay down cylinders of new bone, progressively narrowing the tunnel, which
ultimately becomes the Haversian canal. In trabecular bone, remodelling takes
place at the surface, when osteoclasts burrow a pit which is then filled in by
osteoblasts.
For both types of bone, the
remodelling cycle takes about 200 days. The system is integrated by local
chemical signals which have not yet been fully identified but may involve the
integrins, the RANKL system and calcitonin, PTH and the interleukins. PTH
promotes resorption in order to rectify hypocalcaemia and this triggers
osteoblast action. Osteoblasts have receptors for PTH and this may be part of
the system that activates the osteoblast. Other hormones undoubtedly influence
the system. Estrogens, for example, directly inhibit osteoclastogenensis and
have other regulatory effects on osteoblasts and bone marrow stromal cells.
Estrogens reveal their profound influence through the osteoporosis which may
follow their absence after menopause (see Chapter 54).
