Musculoskeletal Disorders. Sean Gallagher
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lining cells, osteocytes, and osteoclasts (Figure 3.17). They also contain nervous tissue, epithelial cells, and various types of hematopoietic cells. During bone growth and remodeling, there is a delicate balance between osteoblast and osteoclast function. This balance is orchestrated by osteocyte signaling, which dictates the outcome of loading on bone.
Osteoblasts—the producers of bone matrix
Osteoblasts are derived from pluripotent mesenchymal stem cells of the osteochondroprogenitor lineage that have the potential to proliferate and differentiate into several connective tissue cell types depending on the stimulus within the local microenvironment. Given the appropriate stimuli, osteoprogenitor cells will first give rise to preosteoblasts and then osteoblasts (Caplan, 1991; Friedenstein, Chailakhyan, & Gerasimov, 1987; Owen, 1988; Pittenger et al., 1999; Yamaguchi et al., 1991). Osteoblasts are cuboidal mononucleated cells normally found at the bone surface (Figure 3.17a). They are responsible for the synthesis of the organic components of the bone matrix (the osteoid) and mediate its mineralization. Osteoblasts also produce a variety of other noncollagenous proteins, including osteocalcin (which is often used as a serum marker of bone formation). Osteoblasts are an important source of receptor‐activated nuclear factor kappa B ligand (RANKL) that stimulates the differentiation and activation of osteoclasts (Boyce & Xing, 2007). Once osteoblasts become trapped and encased within the mineralized matrix, they are called osteocytes (Figure 3.17a,c).
Figure 3.17 Bone cells. (a) Osteoblasts on the surface of trabeculae (larger cuboidal cells) and osteocytes that are embedded within the trabecular bone are depicted. (b) Bone lining cells are flat cells located on the surface of trabeculae. (c) A high power image of osteocytes, this time embedded within cortical bone. (d) Osteoclasts on the surface of trabecular bone.
Bone lining cells—effector cells on standby
Bone lining cells originate from the same lineage as osteoblasts. They are mononucleated, flattened cells found lining surfaces in areas where there is no active bone formation (Figure 3.17b). They are believed to be a source of already committed osteogenic cells, known as dormant osteoblasts. They can be reactivated to the secreting form with the proper stimulus and under conditions that warrant active bone formation such as during mechanical stimulation, remodeling, and fracture repair (Miller, de Saint‐Georges, Bowman, & Jee, 1989).
Osteocytes—the mechanotransducers and maintainers of bone
Osteocytes are mature bone cells that live within the substance of bone and comprise 90–95% of all bone cells (Bonewald, 2007). Osteocytes are embedded in spaces (lacunae) in the interior of bone and are connected to adjacent cells by long cytoplasmic processes radiating from the cell body that lie within channels (canaliculi) throughout the mineralized matrix of bone (Figure 3.17) (Hirose et al., 2007; Lian & Stein, 2008). The processes of adjacent osteocytes make contact via gap junctions as well as with the osteoblasts and bone lining cells, maintaining the vitality of osteocytes by passing nutrients and metabolites between blood vessels and distant osteocytes (Jiang, Siller‐Jackson, & Burra, 2007).
Osteocytes are believed to be the bone‐sensing cells involved in mechanotransduction and thus the key regulators of bone remodeling. The gap junctions mentioned earlier aid in this function. Also, the osteocyte cell membrane is surrounded by interstitial fluid and extracellular matrix in which microtubules are embedded in order to transmit extracellular matrix mechanical changes to the osteocyte’s actin filaments (Bakker et al., 2009). Osteocytes also communicate with surrounding cells via the release of biochemical factors and signaling molecules, such as bone morphogenetic proteins (BMPs), prostaglandin E2 (PGE2), and nitric oxide (NO) (Klein‐Nulend, Bacabac, & Bakker, 2012).
Osteocytes are also actively involved in maintaining the bony matrix. They express osteoblast stimulating factor‐1 after mechanical or muscular loading (Klein‐Nulend & Bonewald, 2008). Osteocytes send inhibitory signals to osteoclasts to prevent bone loss during normal loading (Nakashima et al., 2011). Local damage (microcracks) of the osteoid matrix can compromise the osteocyte environment, disrupting the fluid flow, consequently reducing nutrients and oxygen supply to the embedded cells and creating oxidative stress (Al‐Dujaili et al., 2011).
Osteoclasts—reallocate and remodel bone
Osteoclasts differentiate after the fusion of bone marrow‐derived mononuclear precursor cells of the monocyte–macrophage lineage in a process termed osteoclastogenesis. Osteoclasts are large multinucleated cells with a ruffled bottom in contact with the bone matrix (Figure 3.17d). They work in concert with osteoblasts in the constant turnover and remodeling of bone. They do this via their ability to secrete hydrochloric acid and other degradative enzymes, which, once activated, dissolve the bone matrix, creating a resorption pit underneath the cell. Osteoclasts are regulated by parathyroid hormone, calcitonin (from the thyroid gland), and pro‐inflammatory cytokines (Boyce & Xing, 2007; Brabnikova Maresova, Pavelka, & Stepan, 2013; Nakashima & Takayanagi, 2011). As mentioned earlier, osteoclast activation is also mediated by the binding of osteoblast or osteocyte produced RANKL (a protein that plays an essential role in the recruitment, differentiation, activation, and survival of osteoclasts) (Burgess et al., 1999). Estrogen has a dual effect: Its presence increases bone formation and reduces bone resorption by enhancing osteoblast proliferation and function (Ernst, Heath, & Rodan, 1989; Majeska, Ryaby, & Einhorn, 1994); it also reduces bone turnover by reducing osteoclast activity (Hofbauer et al., 1999).
Extracellular matrix
Bone is a material constructed of a flexible collagenous matrix that is intermingled with rigid mineral crystals. Thus, bone is harder and less pliable than tendons or cartilage. The extracellular matrix of bone is produced by osteoblasts and consists of inorganic and organic components. For example, osteoid is defined as the unmineralized, organic portion of the bone matrix that forms prior to the maturation of bone tissue; it is composed primarily of collagen type I. In both unmineralized and mineralized bone, the organic component of bone (40% of bone’s dry weight) include collagen type I fibers (90% of the organic matrix and ~97% of the collagenous proteins) and a number of noncollagenous proteins, such as osteocalcin and bone sialoprotein, which may orchestrate mineralization (Hu, Peel, Ho, Sandor, & Clokie, 2009; Robey et al., 1993). The inorganic component of bone represents about 60% of the dry weight of bone matrix and is composed mainly of abundant calcium and phosphorus, as well as smaller amounts of bicarbonate, citrate, magnesium, potassium, and sodium. Calcium forms hydroxyapatite crystals with phosphorus, although it is also present in an amorphous form (Junqueira & Carneiro, 2005; Khurana, 2009). Calcium hydroxyapatite crystals are arranged parallel to collagen fibers. This orientation maximizes the collagen’s resistance to tensile (stretch) forces and calcium hydroxyapatite’s resistance to compressive forces (Gartner & Hiatt, 2007; Sela, Amir, Schwartz, & Weinberg, 1987). In life, bones also have a large amount of water (~25% of the total bone weight) (Ailavajhala, Oswald, Rajapakse, & Pleshko, 2019; Ailavajhala, Querido, Rajapakse, & Pleshko, 2020).
Organization
According to their anatomical shape, bones are classified into four general categories: long, short, flat, and irregular bones. We will focus here on long bones. Long bones have two extremities