Friday, November 21, 2014

Bone Metabolism: Bone formation and bone resorption (Part 1)


Fig. Bone Cells
Living bone is constantly being remodeled. The state of our bones is always close to an equilibrium between bone formation and bone resorption. In childhood and during the teens, bone formation is slightly ahead. We reach peak bone mass in the twenties, and from then onwards, resorption has the upper hand. There are two reasons for the
constant remodeling process. Firstly, it allows our bones to adapt to changes in load. For example, consider how easily skilled orthodontists maneuver teeth in the jaw bone by applying modest targeted strain. Secondly, continuous remodeling is necessary to repair the damage caused by recurrent microtraumas. At a typical remodeling site, termed basic multicellular unit, specialized osteoclasts first remove bone over a period of approximately three weeks. The resulting resorption lacuna is subsequently filled by osteoblasts, a process lasting about three months. Bone tissue is found in two forms: substantia compacta and substantia spongiosa. As much weight is saved as possible: only the outer contour, the cortical compact bone, is massive. The inner part is made up of trabecular, or cancellous bone, a three-dimensional scaffold of pillars and beams that is constantly modified to accommodate load. Prominent examples of cancellous bone are found in vertebral bodies or at the ends of long bones.

The fundamental unit of compact bone is the osteon or Havers system. A central vascular canal is surrounded by massive concentric lamellae of mineralized fibers. In consecutive lamellae, matrix fibers are arranged in spirals with alternating sense of rotation, contributing to mechanical strength. Encased bone cells, osteocytes, are interspersed between lamellae.

In essence, bone metabolism is due to only two types of cells: osteoblasts and osteoclasts. Osteocytes are simply osteoblasts that have encased themselves in bone. Individual osteocytes remain connected by long cellular processes, forming a network connected by gap junctions. Osteocytes are able to sense mechanical strain, which they report to the bone construction units via this network.

Osteoblasts differentiate from stromal marrow cells. They produce the organic part of the bone matrix, an array of proteins collectively termed osteoid. In the following, a look at three out of a much larger number of these proteins:

Fig. Composition of Aricular cartilage 
1.   Collagen type I represents the bulk of osteoid. It consists of triple helix units containing two α1-chains and one α2 chain, which already form in the endoplasmic reticulum of the osteoblast after the individual chains have been posttranslationally hydroxylated on lysines and prolines. This procollagen unit is secreted, followed by proteolytic removal of C- and N-terminal peptides. The resulting collagen monomers spontaneously aggregate in a staggered fashion, forming long fibrils that are subsequently covalently cross linked via their hydroxylated lysines. A cofactor required for lysine and proline hydroxylation is vitamin C. Lack of vitamin C results in scurvy, characterized by collagen that is instable due to insufficient cross linking.

2.    Osteocalcin is a small protein that is carboxylated on glutamic acid residues with the help of vitamin K. As glutamate already contains one COO --group, carboxylation of the γ-C-Atom creates a second one right next to the first. The two adjacent negative charges are ideal docking sites for double positive Ca2+ ions. Ca2+ is thus locally concentrated in the bone and, with the help of integrin-binding sialoprotein, nucleates crystals with phosphate ions to form hydroxyapatite Ca5(PO4)3(OH). The process makes sure that Ca2+ and phosphate precipitate in the bone and not in other tissues of the body. Vitamin K is also necessary to carboxylate clotting factors II, VII, IX, X, providing them with functionally essential Ca2+ binding sites. Therefore, deficiency of vitamin K results in bleeding disorder long before effects on bone might cause problems. A second vitamin is important for osteocalcin: the transcription of its gene is induced by activated vitamin D receptor. Osteocalcin itself has a second function, too. A proportion of non-carboxylated osteocalcin enters the blood stream and functions as a metabolic hormone enhancing insulin activity. It stimulates proliferation of pancreatic β-cells, and sensitizes fat cells to insulin by stimulating them to secrete adiponectin. Via this mechanism, bone metabolism influences energy metabolism.

3.   Osteonectin is an osteoid component that makes contact to collagen type I as well as to hydroxyapatite, forming a link between organic and inorganic bone matrix.

In addition, osteoblasts engage in targeted export of Ca2+ and phosphate, inducing local super saturation conditions to mineralize the freshly produced osteoid. For this process, alkaline phosphatase tethered to the outside of the osteoblast plasma membrane seems to be important, though the enzyme's role remains insufficiently understood. It may increase extracellular phosphate concentration by dephosphorylating organic molecules or cleaving pyrophosphate.

Osteoclasts are giant, multinucleated cells that derive from hematopoietic stem cells in the bone marrow, branching from the lineage leading to macrophages and neutrophils. A series of cytokines induces precursor cells to differentiate to osteoclasts. The basic mix combines M-CSF (macrophage colony stimulating factor) with RANKL (explained in the following section on parathyroid hormone), two cytokines produced by osteoblasts. In addition, mediators produced by macrophages and other cells during inflammatory responses enhance osteoclast differentiation: IL-1, IL-6 , TNFα and prostaglandin E. Osteoclasts break down bone tissue much like macrophages break down phagocytosed material; only the process is shifted to the extracellular space. Employing normal lysosomal chemistry, it involves acidification and activation of acid hydrolases. Osteoclasts seal off a certain matrix area, which they acidify with the help of a proton pump. To maintain intracellular pH, they release HCO3- at their back side. Hydroxyapatite dissolves in the acidic environment, setting free Ca2+  Thus, on the scale of the entire body, an orchestrated activation of osteoclasts is a means to increase extracellular Ca2+ concentration. After the mineral has melted away, acid proteases like Cathepsin K hydrolyze the remaining matrix proteins.

Growth of long bones is not possible in bone tissue itself, but happens in epiphyseal cartilage. Driven by growth hormone and other hormones (see below), chondrocytes proliferate and increase their production of cartilage. At the border zone, the cartilaginous tissue is first simply mineralized (enchondral ossification), but soon remodeled to osteon structure by immigrating osteoclasts and osteoblasts. A second ossification mechanism, intramembranous ossification, is the direct transformation of fibrous mesenchymal tissue to bone. This type of ossification is found in the development of large parts of the skull, as well as in healing of bone fractures.

(Credit: Arno Helmberg)
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