Chapter 2 Literature review
2.3 Bone growth, modeling and remodeling
Bone undergoes longitudinal and radial growth and modeling during adolescence and young adulthood until skeletal maturity is reached. Bone modeling, in which bone formation and resorption are not tightly coupled, results in a change in bone shape and size. Bone remodeling in contrast, is a continuous ongoing renewal process, in which trabecular micro-damage is repaired. Discrete units of old bone are removed and replaced by new bone in a closely interrelated cycle [95] in a bone structural unit (BSU). The cycle has 5 steps (Figure 2.1) and takes approximately 3 -
6 months to complete and is regulated by cytokines, growth factors and mechanical stimuli [95].
Activation of the cycle occurs when monocytes are attracted to resting bone by stimuli including hormones and cytokines. Matrix metalloproteinases digest the thin collagenous membrane. Thereafter osteoclasts are recruited, bone is resorbed forming a cavity known as the “Howship lacunae” and calcium is released into blood.
This process occurs takes approximately 2 - 4 weeks [99]. In the reversal phase unknown cells repair the erosion by lining it with a thin layer of cement.
Subsequently osteoblasts lay down a new matrix which is then mineralized. In the resting phase, remodeling is complete and osteoblasts trapped in the BSU change to osteocytes.
Activation Resorption Reversal
Resting Formation
Figure 2.1 Diagrammatic summary of the 5 cycles in bone remodeling
Adapted from Arden 2006 [95]
2.3.1 Regulation of bone growth, modeling and remodeling
Cells involved in bone modeling and remodeling
Osteoblasts, derived from pluripotent stromal stem cells, are the bone lining cells responsible for the synthesis and secretion of the organic bone matrix and bone mineralization. Their growth and functioning is controlled by core binding factor A1 and Indian hedgehog [95, 100], which regulate the expression of osteoblast specific genes including osteocalcin, osteopontin, bone sialoprotein, and receptor activator of nuclear factor-κβ ligand (RANKL). Osteoblasts express receptors for parathyroid hormone (PTH) and 1, 25 - dihydroxyvitamin D (1, 25 (OH)2 D) which play an important role in calcium homeostasis [99].
Osteocytes act as mechanosensors and initiate the remodeling process via nitric oxide (NO), insulin like growth factor (IGF) and glucose-6-dehydrogenase [101].
They also respond to changes in PTH and calcitonin levels, and therefore play a role in maintaining body calcium levels [95].
Osteoclasts are large multinucleated cells derived from the monocyte/macrophage lineage cells and are responsible for bone resorption [95, 102, 103]. Their development and growth is regulated by macrophage colony stimulating factor (m- CSF) and RANKL found on osteoblast progenitor cells and stromal fibroblasts. The binding of RANKL to its receptor activator of nuclear factor-κβ (RANK), expressed by osteoclasts, initiates and stimulates osteoclast differentiation. In contrast, when RANKL binds to osteoprotegerin (OPG), a soluble decoy receptor secreted by osteoblasts, osteoclast differentiation is inhibited [103-105]. The ratio of
OPG/RANKL is critical in determining bone mass and lower levels of OPG are associated with decreased bone mass. Osteoprotegerin levels decrease with age, at menopause and in glucocorticoid induced osteoporosis. Osteoclast apoptosis is inhibited by PTH, 1, 25 (OH)2 D, interleukin 1(IL1), interleukin 6 (IL6), m-CSF, tumour necrosis factor alpha (TNF-α) and RANKL while transforming growth factor beta (TGF-β) and OPG stimulate osteoclast apoptosis [106].
Physical stimuli and muscle action both influence bone remodeling and according to Wolff’s law, “bone accommodates the load placed on it by altering its mass and distribution of mass” [107]. There is a positive linear relationship between physical activity and bone mass, namely chronically increased mechanical load on bone increases bone mass, while a decreased load results in bone loss.
Vitamin D is important for homeostasis and bone metabolism. It maintains extracellular calcium concentrations by controlling absorption of calcium and by direct effects on bone and on PTH secretion. Parathyroid hormone acts directly and indirectly on the osteoclasts to increase bone resorption and skeletal calcium mobilization [108]. In the kidney it decreases calcium excretion and increases the formation of 1, 25 (OH)2 D3 which in turn, increases intestinal calcium absorption.
Continuous administration of PTH leads to bone loss but intermittent administration has an anabolic effect [95].
Calcitonin directly inhibits bone resorption by its action on both precursor and mature osteoclasts by decreasing the ruffled borders of osteoclasts and increasing cyclic adenosine monophosphate (cAMP) [95, 103].
Sex hormones
Oestrogen inhibits bone resorption by acting directly on receptors found on osteoclasts to enhance osteoclast apoptosis and indirectly by blocking pro- inflammatory cytokines. It also acts directly on osteoblasts to increase OPG [101, 109, 110] and indirectly on osteocytes, bone marrow megakaryocytes and mononuclear cells [111]. Oestrogen actions on bone include decreasing the pro- resorptive cytokines, RANKL and TNF-α, increasing antagonists IL1, TGF- β and OPG, and increasing serum calcium by increasing intestinal calcium absorption and decreasing renal calcium excretion. Oestrogen deficiency results in rapid bone loss especially after menopause due to an increase in the rate of bone remodeling with an imbalance between resorption and formation of BSU, leading to formation of unfilled bone cavities [112].
Testosterone acts directly on bone via androgen receptors found on osteoblasts and is responsible for the increase skeletal growth seen at puberty in boys. In males oestrogens derived from androgen are important for normal bone development similar to oestrogen in women. The importance of oestrogen for normal skeletal growth in males is supported by the failure to achieve normal skeletal growth in males with oestrogen receptor (ER) resistance despite normal testosterone levels [95]. Oestrogen is also important in the maintenance of normal bone mass in older men [113].
Glucocorticoids (GC) have direct and indirect effects on bone via GC receptors.
They inhibit osteoblast activity and generation whilst increasing osteoclast activity
and decreasing osteoclast apoptosis. This results in an increase in RANKL and decrease in OPG levels [95, 114, 115].
Other systemic hormones which influence bone metabolism include growth hormone (GH), thyroid hormone and leptin. Growth hormone acts primarily via IGF to increase bone turnover and bone mass [95]. Excess thyroid hormone levels stimulate bone resorption, hypercalcaemia and decrease PTH and vitamin D levels [95]. While leptin, an adipocyte derived hormone, increases osteoblast differentiation and inhibits osteoclasts, its relevance in humans has not been proven [116-118].