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 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).