Alveolar bone is the mineralized connective tissue that supports and protects the teeth. Similar to bone elsewhere, it also provides for muscle attachment and contains bone marrow. The most important property of bone is its ‘plasticity’, allowing it to remodel according to the functional demands placed on it. There are five main types of bone cell and the basic unit of bone is the osteon (Haversian system). The processes of bone resorption and formation at sites of remodelling do not occur randomly. There must be tight control to ensure a balance between the two processes (coupling), as any disruption of this balance can lead to bone disease.
• know the composition, classification and main structural features of bone
• be familiar with the various cell types and understand how their structure is related to function
• be aware of the principles that regulate bone formation and resorption and how these processes are coupled
• understand why a considerable knowledge of bone is necessary to appreciate the many ways it impinges on the clinical situation.
The part of the maxilla or mandible that supports and protects the teeth is known as alveolar bone. An arbitrary boundary at the level of the root apices of the teeth separates the alveolar processes from the body of the mandible or the maxilla. Like bone in other sites, alveolar bone functions as a mineralized supporting tissue, giving attachment to muscles, providing a framework for bone marrow, and acting as a reservoir for ions (especially calcium). Apart from its obvious strength, one of the most important biological properties of bone is its ‘plasticity’, allowing it to model/remodel according to the functional demands placed upon it. Bone depends on function (i.e. mechanical stimuli) to maintain its structure and mass.
Bone is a mineralized connective tissue. Approximately 60% of the wet weight of bone is inorganic mineral, with 25% organic matrix and the remaining 15% water. The mineral phase provides the hardness and rigidity of bone and consists of carbonated hydroxyapatite, present in the form of thin needle-like crystallites or thin plates (about 50 nm wide, up to 8 nm thick and of variable length) distributed between the gap zones of the collagen molecules. The organic matrix contributes to other aspects of its physical properties, such as tensile strength and modulus of elasticity, and is approximately 90% type I collagen. Most collagen can be regarded as intrinsic collagen secreted by osteoblasts. However, collagen inserted as Sharpey fibres from the periodontal ligament can be considered as extrinsic collagen. The non-collagenous matrix is a heterogenous group of proteins, which accounts for 10% of the organic matrix. These proteins include the proteoglycans, which incorporate chondroitin and heparan sulphate glycosaminoglycans, mainly in the form of decorin and biglycan. Glycoproteins associated with bone include osteopontin, osteonectin, bone sialoprotein (BSP), osteocalcin and fibronectin. The part played by these individual proteoglycans still requires clarification; however, they may have important roles in bone formation and subsequent mineralization. Bone also contains exogenously derived proteins that may circulate in the blood. These include albumin and also a varied cocktail of cytokines and growth factors, including interleukins, tumour necrosis factor, TGF-β, FGF, PDGF and BMPs. These bioactive molecules are stored or locked up within the bone matrix. Release of these molecules during trauma or general remodelling may play a role in controlling further bone activity.
There are a number of ways that the classification of bone can be achieved:
• Developmentally, there is endochondral bone (where bone is preceded by a cartilaginous model that is eventually replaced by bone in a process termed endochondral ossification) and intramembranous bone (where bone forms directly within a vascular, fibrous membrane).
• Histologically, mature bone may be categorized as compact (cortical) or cancellous (spongy), according to its density. As the names suggest, compact bone forms a dense, solid mass, while in spongy bone there is a lattice arrangement of the individual bony trabeculae that surround bone marrow.
• In newly formed bone, the collagen fibres have a more variable diameter and lack a preferential orientation, giving the bone a matted (basketweave) structure. This immature bone, termed woven bone, has larger and more numerous osteocytes. Woven bone is subsequently converted to fine-fibred, adult lamellar bone.
The alveolar, tooth-bearing portion of the jaws is composed of outer and inner alveolar plates. The individual sockets are separated by plates of bone termed the interdental septa, while the roots of multirooted teeth are divided by inter-radicular septa. The compact layer of bone lining the tooth socket has been referred to as the cribriform plate, reflecting the sieve-like appearance produced by the numerous vascular canals (Volkmann’s canals) passing between the alveolar bone and the periodontal ligament. It has also been called bundle bone because numerous bundles of Sharpey fibres pass into it from the periodontal ligament. In clinical radiographs, the bone lining the alveolus commonly appears as a dense white line and is given the name lamina dura. Between the bundle bone and the inner and outer plates of compact bone are variable amounts of spongy bone, depending on site.
Bone is deposited in layers, or lamellae, each being 3–5 μm thick.
In compact bone the lamellae are arranged in two major patterns:
• At external (periosteal) and internal (endosteal) surfaces, they are arranged in parallel layers completely surrounding the bony surfaces and are known as circumferential lamellae.
• Deep to the circumferential lamellae, the lamellae are arranged as small, concentric layers around a central neurovascular canal. The central canal (about 50 μm in diameter), together with the concentric lamellae, is known as an osteon or Haversian system.
There may be up to about 20 concentric lamellae within each Haversian system, the number being limited by the ability of nutrients to diffuse from the central vessel to the cells in the outermost lamella. A cement line of mineralized matrix delineates each Haversian system. The collagen fibres within each lamella are parallel to one another and spiral along the length of the lamella, but have a different orientation to those in the adjacent lamella. As a consequence of remodelling, fragments of previous Haversian systems (interstitial lamellae) may be present.
In spongy bone, the lamellae are apposed to each other to form trabeculae up to about 50 μm thick, surrounded by the marrow spaces. The trabeculae are not arranged randomly but are aligned along lines of stress so as best to withstand the forces applied to the bone while adding minimally to mass.
In young bone, the marrow is red and haemopoietic. It contains stem cells of both the fibroblastic/mesenchymal type (capable of giving rise to fibroblasts, osteoblasts, adipocytes, chondroblasts and myoblasts) and blood cell lineage (capable of giving rise to osteoclasts). In old bone, the marrow is yellow, with loss of haemopoietic potential and increased accumulation of fat cells.
Any surface where active bone formation is occurring will be covered by a layer of newly deposited, unmineralized, bone matrix called osteoid, having a thickness of approximately 5–10 μm. This represents an initial deposition of unmineralized matrix. Like predentine, osteoid will stain differently from the matrix associated with mineralized bone, indicating that biochemical changes take place within the matrix at the mineralizing front to enable mineralization to occur; some molecules may be added, others may be degraded. Osteoid contains a cocktail of cytokines and growth factors in a collagen matrix. Collagen is present as type I collagen arranged parallel to the bone surface. Traces of collagen type III are present at Sharpey fibre insertions. The collagen is embedded in a non-collagenous matrix rich in proteoglycans, including dermatan sulphate-substituted forms of decorin and biglycan. These two proteoglycans are thought to have roles in cell differentiation, proliferation and matrix assembly. Other glycoproteins also present within this unmineralized matrix include:
• versican, a large interstitial proteoglycan associated with capture of space
• fibronectin and tenascin, usually associated with soft connective tissues, which are evident at Sharpey’s insertion points and have roles in matrix formation and cell adhesion.
Initial mineralization of osteoid may be controlled by matrix vesicles, which bud off from the osteoblast cell membrane. These vesicles contain the initial mineral crystals and the membrane around these crystals breaks down to form the seed around which extensive mineralization occurs by epitaxy or heterogenous nucleation. Significant remodelling and biochemical changes occur within the osteoid prior to mineralization and that accounts for the perceived lag phase before the deepest layer of osteoid undergoes mineralization.
Bone contains several different cell types that are responsible for the synthesis, maintenance and resorption of bone. They can be regarded as belonging to two main families, one mesenchymal and the other haemopoietic:
• The osteoblasts, osteocytes and bone-lining cells are derived from a mesenchymal (or ectomesenchymal) stem cell.
• Osteoclasts, however, are derived from a haemopoietic source, the macrophage/monocyte lineage.
A layer of osteoblasts is prominent on bone surfaces where there is active bone formation. They appear cuboidal and exhibit conspicuous amounts of endoplasmic reticulum and Golgi material within the cells. Osteoblasts are also in contact with underlying osteocytes. Osteoblasts secrete the organic matrix of bone that initially is represented by an unmineralized layer, the osteoid. Useful markers of the osteoblast phenotype include osteocalcin and osteoblast transcription factor, Runx2 (Cbfa-1). Alkaline phosphatase activity, although not entirely specific to bone, is also a reliable indicator of osteoblastic differentiation. The secreted, intrinsic collagen fibrils lie parallel to the bone surface. At the surface of alveolar bone adjacent to the periodontal ligament, extrinsic Sharpey fibres pass more or less perpendicularly into the osteoid layer. In addition to secreting the formative components of bone, the osteoblast secretes molecules controlling its own activity (such as growth factors, cytokines and prostaglandins) and that of the osteoclast.
Osteocytes are postmitotic cells lying within the bone itself and represent ‘entrapped’ osteoblasts. However, compared with osteoblasts, they show a considerable reduction in the intracellular organelles associated with protein synthesis. Osteocytes play an important role in calcium homeostasis. They are housed in lacunae, possess numerous cell processes that run in channels (canaliculi) within bone, and link up with the processes of neighbouring osteocytes at gap junctions. The superficially situated osteocytes are in contact with cells lining the bone surface. The cell processes in the canaliculi allow the diffusion of substances from adjacent blood vessels throughout the bone.
As a result of their widespread distribution in bone and their interconnections, osteocytes are obvious candidates to detect load-induced strains in bone and are therefore regarded as the primary mechanosensors in bone.
When bone surfaces are in neither the formative nor resorptive phase, they are lined by a layer of flattened cells termed bone-lining cells. Like osteoblasts, the bone-lining cells are connected to underlying osteocytes. They show little sign of synthetic activity and may be regarded as post-proliferative osteoblasts. By covering the surface of bone, they may:
• play a role in calcium and phosphate metabolism
• protect the surface from any resorptive activity by osteoclasts
• participate in initiating bone remodelling.
In order to generate osteoblasts throughout life, a stem-cell population is required. Stem cells have the ability to maintain their numbers throughout life. They reside in the layer of cells beneath the osteoblast layer in the periosteal region, in the periodontal ligament, or in the adjacent marrow spaces.
Osteoclasts are derived from fusion of haemopoietic cells of the macrophage/monocyte lineage, giving rise to multinucleated cells. Osteoclasts are highly motile. Their lifespan is not known with certainty, although it is thought to be between 10 and 14 days, after which the cells undergo apoptosis. Resorbing surfaces of alveolar bone show typical resorption concavities (Howship’s lacunae) in which the osteoclasts lie. A useful marker for osteoclasts is the enzyme tartrate-resistant acid phosphatase.
Characteristically, human osteoclasts may be up to 100 μm in diameter and have on average 10–20 nuclei. When actively resorbing, osteoclasts possess a ruffled border composed of many tightly packed microvilli adjacent to the bone surface, providing a large surface area for the resorptive process. A sealing (clear) zone surrounds the periphery of the ruffled border. Here, the plasma membrane is smooth and the organelle-free cytoplasm beneath it contains numerous contractile actin microfilaments (surrounded by two vinculin rings). The sealing zone serves to attach the cell very closely to the surface of bone, mainly due to the presence of cell membrane adhesion proteins known as integrins. The osteoclast contains numerous mitochondria and large numbers of vesicles of different sizes and types, some containing lysosomal enzymes capable of degrading the organic matrix of bone. Once the osteoclast has been activated, bone resorption occurs in two stages. Initially, the mineral phase is removed and later the organic matrix.
Extrinsic Sharpey fibres inserting into the cribriform plate are derived from the principal fibres of the periodontal ligament. Sharpey fibres are particularly prominent in the cervical portion (alveolar crest region) of the alveolar bone. Here, where bone is compact, Sharpey fibres may penetrate the bone to a considerable depth. Sharpey fibres entering alveolar bone are less numerous but thicker than those at the cementum surface. Because of the attachments of numerous bundles of collagen fibres, the cribriform plate has also been called bundle bone.
Structural lines are evident in bone. Bone is laid down rhythmically, which results in the formation of regular parallel lines that, because they are formed in periods of relative quiescence, are termed resting lines. Such resting lines differ biochemically from adjacent bone. These lines are prominent in bundle bone on the distal surface of the socket wall during physiological mesial drift of the teeth. Bone will also contain reversal lines, representing the site of change from bone resorption to bone deposition. Such reversal lines will show evidence of a scalloped outline, reflecting the position of Howship’s lacunae.
Resorption and deposition of bone
There is close correlation between resorption and deposition of bone. The osteoclast has far fewer surface receptors than the osteoblast and is not directly responsive to the majority of hormones or growth factors. This has led to the concept that the osteoblast has a controlling influence in the development and maturation of the osteoclast. However, important receptors that the osteoclast does express are those for calcitonin (a powerful inhibitor of osteoclasis that interferes with the cell attachment mechanism to bone), prostaglandins and RANK (receptor activator of nuclear factor kappa B).
The processes of bone resorption and formation at sites of remodelling do not occur randomly. Clearly, there must be tight control to ensure a balance between the two processes, as any disruption of this balance can lead to metabolic bone disease (such as osteopetrosis and osteoporosis). This close control can be referred to as coupling. From a resting state, the sequence of remodelling consists of four main phases:
• Resorption: recruitment, migration and activation of osteoclasts, causing bone resorption.
• Reversal: cessation of resorption and disappearance of osteoclasts. The site becomes occupied by mononuclear cells. The changeover from resorption to deposition is characterized by a reversal line.
• Formation: osteoblast recruitment, migration, differentiation and formation of new bone in the resorption site.
• Resting: formation of bone ceases and the surface is lined by a flattened layer of bone-lining cells.
There is thus a clear relationship between bone deposition and bone resorption, and this relationship is mediated biochemically. Many of the factors that result in bone resorption do not have direct effects on osteoclasts but act through osteoblasts, as most receptors to the bioactive molecules responsible for resorption are present on the osteoblast. How the osteoblast promotes resorption may be through the release of bioactive proteins such as cytokines and growth factors, including macrophage colony stimulating factor (MSC-F), osteoprotegerin, receptor activator of nuclear factor kappa B ligand (RANKL), and interleukins, which may stimulate the production of osteoclasts. Osteoblasts may release MMPs, degrading the osteoid on the bone surface, exposing the mineralized bone matrix, and allowing osteoclasts to attach themselves to the mineralized bone and begin resorption. Whilst the precise signals responsible for causing the cessation of resorption and a reversal to osteoblast differentiation and activation of bone formation are not known, the release of molecules such as growth factors, initially bound up in the bone matrix but exposed/activated by the resorption process, may be involved. For example, BMPs and IGF released from bone may stimulate osteoblastogenesis, while TGF-β released from bone may inhibit osteoclastogenesis while stimulating osteoblastogenesis. These bone-bound bioactive growth factors are activated by subsequent osteoclastic bone resorption and bind to their receptors on osteoblasts and osteoclasts, influencing bone remodelling. Ambient pH and levels of oxygen are also important factors affecting resorption.
As a reduction in the mechanical loads impinging on bone is associated with bone loss, it can be assumed that such loading is normally required to stimulate the modelling/remodelling processes of bone necessary to maintain normal bone structure. Strains need to be intermittent (rather than continuous), and the osteogenic response is dependent upon the size of the load and the frequency and rate of application. To maintain bone mass may only require the application of relatively few loading cycles.
The molecular mechanisms whereby forces impinging on the bone are transduced into bone resorption or deposition remain elusive, although many theories have been proposed. Osteocytes, together with the surface layer of osteoblasts/bone-lining cells, appear to be the most obvious candidates for detecting strain within bone. Deformation of bone following loading is thought to deform the cell processes/cell membranes either directly, or indirectly through movement of tissue fluid residing in the lacuno-canalicular system. Signals are then transduced via the cell membrane at the surface (e.g. involving K +
and Ca 2+
ion channels and integrins) to cytoskeletal elements within the cell, with stimulation of secondary messengers. These changes eventually lead to the production and release of molecules that initiate an osteogenic response.
Osteoblast formation is initiated from pluripotent mesenchymal stem cells. These cells give rise to intermediate progenitor cells that form osteoprogenitors (immature and mature forms) and pre-osteoblasts. It takes about eight cell divisions before an osteoblast finally differentiates to form an osteoid seam that mineralizes to produce bone. Among the earliest markers to indicate that a stem cell is progressing along an osteogenic phenotype is the expression of the nuclear transcription factor, core binding factor 1 (Cbfa1, also called Runx2). This is responsible for regulating the production of a number of important protein products in bone matrix. The induction of Cbfa1 involves/>
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