Physiology and pathophysiology of bone remodeling. Clinical chemistry, 45 8B : PTH is a stimulator of bone resorption and 1,Dihydroxy vitamin D has its greatest effect on intestinal calcium and phosphate absorption, but it may also have direct effects on bone and other tissues.
It is probably critical for the differentiation of both osteoblasts and osteoclasts and can stimulate bone resorption and formation under some experimental conditions. A third hormone, calcitonin Table 1 , in contrast to PTH and 1,25 OH 2 D3, both of which increase calcium release from the mineralized matrix, calcitonin is an inhibitor of osteoclast activity. It is a potent inhibitor of bone resorption and is used clinically in the treatment of bone diseases.
Other systemic hormones are keys in regulating bone remodeling, such as: Growth hormone acting through both systemic and local insulin-like growth factor IGF production, can stimulate bone formation and resorption. Glucocorticoids are necessary for bone cell differentiation during development. Indirect effects of glucocorticoids on calcium absorption and sex hormone production may, however, increase bone resorption Table 1.
O the other hand, probably the most important systemic hormone in maintaining normal bone turnover is estrogen. Estrogen deficiency leads to an increase in bone remodeling in which resorption overcome formation and bone mass decreases Table 1. The increase in bone remodeling and in bone resorption in the estrogen deficient state is associated with an increase in bone formation at the tissue level [ 51 ].
Therefore, sex steroid deficiency is associated with a defect in bone formation. Based on the available evidence, there are currently at least three key mechanisms by which estrogen deficiency may lead to a relative deficit in bone formation through direct effects on osteoblasts: increased apoptosis, increased oxidative stress, and an increase in NF-kB activity Figure 3.
In addition, estrogen inhibits the activation of bone remodeling, and this effect is most likely mediated via the osteocyte [ 52 ]. The parathyroid hormone PTH increases bone formation in bone diseases. PTH induces the synthesis of IGF-I that works with PTH in osteoblasts to stimulate osteoblast proliferation and differentiation as well as indirectly regulates osteoclast activity [ 54 , 55 ].
Also, PTH was inferred to interact with various local signaling molecules, including insulin-like growth factors and Wnt antagonist sclerostin SOST [ 55 - 57 ]. This does not exclude the possibility that PTH receptor signaling may increase bone mass and bone remodeling by affecting Wnt signaling in other cell types.
Recent data indicate that the activation of the PTH receptor in T lymphocytes plays a role in PTH-induced bone formation and bone mass by promoting the production of Wnt10b by these cells [ 59 ]. The in vivo stimulation of the Wnt10b signaling cascade in the FABP4 promoter-Wnt10b transgenic mice led to a significantly higher bone mass because of the stimulation of osteoblastogenesis and the inhibition of adipogenesis. Recent advances have been made in our understanding of the role of Wnt proteins in bone cell biology.
It was found that, in addition to Wnt10b [ 63 ], several other Wnt proteins Wnt6a, Wn10a influence the differentiation of mesenchymal precursors into osteoblasts or adipocytes, and thereby control bone mass [ 64 ]. The Wnt signal is modulated by various antagonists, including secreted factors, transmembrane modulators, and intracellular signals. Dickkopf family members Dkk1 and Dkk2 and secreted frizzled related proteins Sfrps are families of extracellular proteins that negatively modulate canonical Wnt signalling [ 60 ].
These signals are transduced together by the activation of R-smads and Cosmads as well as through the mitogen-activated protein kinase MAPK pathway Table 2. Bone morphogenetic proteins BMPs , they are so named for their osteoinductive properties, and regulate differentiation of mesenchymal cells into components of bone, cartilage or adipose tissue.
BMP signaling is modulated by multiple agonists and antagonists acting at the extracellular level, which are also important for bone remodeling and may be potential therapeutic targets [ 69 ]. Key signaling pathways for regulating osteoblastogenesis in bone remodeling.
Leptin—brainstem-derived serotonin-sympathetic nervous system and Sema4D pathway suppresses osteoblast proliferation, whereas gut-derived serotonin inhibits osteoblast proliferation. The interactions between Eph and Ephrin play important roles in bone cell differentiation and patterning by exerting effects on osteoblast and osteoclast differentiation, resulting in the coupling of bone resorption and bone formation.
Eph receptors are tyrosine kinase receptors activated by ligands called ephrins Eph receptor interacting proteins. Both Ephs and ephrins are divided into two A and B groups [ 70 ]. To date, ephrinB2, a transmembrane protein expressed on osteoclasts, and its engagement with its receptor, EphB4, on osteoblasts, lead to bi-directional signaling between these cells; this is one of the cell-cell contact mechanisms that mediate crosstalk between these cells. EphrinB2 as reverse signaling , located on the surface of osteoclast precursors, suppresses osteoclast precursor differentiation by inhibiting the osteoclastogenic c-Fos-NFATc1 cascade Table 2 [ 71 ].
In addition, the signaling mediated by EphB4 as forward signaling located on the surface of osteoblast enhances the osteogenic differentiation. Ephrin B1 induces osteoblast differentiation by transactivating the nuclear location of transcriptional coactivator with PDZ-binding motif TAZ , a co-activating protein of Runx2. TAZ, together with Runx2, induces osteoblast-related gene expression [ 72 ]. Both the reversed signaling EphrinA2 and forward signaling EphA2 stimulate osteoclast differentiation, but EphA2 has a negative role in bone formation by inhibiting osteoblast differentiation through the regulation of RhoA activity Figure 3 [ 71 ].
The epidermal growth factor receptor EGFR is a glycoprotein on the cell surface of a variety of cell types and is characterized by its ligand-dependent tyrosine kinase activity.
After ligand binding to the extracellular domain, the EGFRs are activated by homo- or heterodimerization with auto- and transphosphorylation on tyrosine residues at the intracellular domain, and then a variety of signaling pathways, such as Ras-Raf-MAP-kinase and PI kinase-Akt, are activated to influence cell behaviors, such as proliferation, differentiation, apoptosis, and migration Table 2 [ 73 ].
In recent years, several experiments indicate that the epidermal growth factor receptor EGFR system plays important roles in skeletal biology and pathology. It was recently found that decreasing EGFR expression in pre-osteoblasts and osteoblasts in mice results in decreased trabecular and cortical bone mass as a consequence of reduced osteoblastogenesis and increased bone resorption [ 48 ].
Multiple signaling pathways activated by FGF receptors 1 and 2 control osteoblast proliferation, differentiation, and survival Table 2. Activation of ERK-MAP kinase by activating FGFR2 mutations results in increased transcriptional activity of Runx2, an essential transcription factor involved in osteoblastogenesis, and increased osteogenic marker gene expression Figure 3 [ 77 ]. The Insulin-like growth factor-I IGF-I signaling through its type 1 receptor generates a complex signaling pathway that stimulates cell proliferation, function, and survival in osteoblasts Table 2 [ 81 ].
Recent findings indicate that many of the IGFBPs and specific proteins in the IGF-I signaling pathways are also potent anabolic factors in regulating osteoblast function and may serve as potential targets to stimulate osteoblast function and bone formation locally.
A new regulation mode of osteoblastic bone formation controlled by leptin-serotonin BDS -sympathetic nervous system pathway has emerged in recent years. Leptin is a hormone produced by adipocytes that, besides its function in regulating body weight and gonadal function, can also act as an inhibitor of bone formation Figure 3 [ 84 ]. Latest data indicates that these leptin functions require brainstem-derived serotonin [ 85 ]. Serotonin is a bioamine produced by neurons of the brainstem brainstem-derived serotonin, BDS and enterochromaffin cells of the duodenum gut-derived serotonin, GDS.
There are two Tph genes that catalyze the rate-limiting step in serotonin biosynthesis: Tph1 expressed mostly, but not only, in enterochromaffin cells of the gut and is responsable for the production of peripheral serotonin [ 86 ].
Tph2 is expressed exclusively in raphe neurons of the brainstem and is responsible for the production of serotonin in the brain [ 87 ]. Leptin inhibits BDS synthesis by decreasing the expression of Tph2, a major enzyme involved in serotonin synthesis in brain [ 85 ]. In addition, other data indicate, the key role of GDS in regulating bone formation as well as the relationship between GDS, Lrp5, and bone remodeling. Lrp5 controls bone formation by inhibiting GDS synthesis in the duodenum, and GDS directly acts on the osteoblast cells to inhibit osteoblast proliferation and suppress bone formation Table 2 [ 88 ].
However, recent data to argue that Lrp5 affect bone mass mainly through local Wnt signaling pathway, and that the experiments did not support the Lrp5-GDS-osteoblast model because they found that there was no relevance between GDS and bone mass in their mouse model system [ 89 ].
More recently, other signaling pathways that link regulation of the osteoclasts and osteoblasts have been identified. Osteoblast-lineage cells expressed Wnt5a, whereas osteoclast precursors expressed Ror2.
Connection between these two cells leads to Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhanced osteoclastogenesis, through increased RANK expression mediated by JNK signaling. A soluble form of Ror2 acted as a decoy receptor of Wnt5a and abrogated bone destruction in the mouse model, suggesting that the Wnt5a-Ror2 pathway is crucial for osteoclastogenesis in physiological and pathological environments and may represent a therapeutic target for bone diseases Figure 3 [ 90 ].
Finally, a recent study reported that semaphorin 4D Sema4D , previously shown to be an axon guidance molecule, expressed by osteoclasts and which potently inhibits bone formation [ 91 ]. Several studies have suggested that axon-guidance molecules, such as the semaphorins and ephrins, are involved in the cell-cell communication that occurs between osteoclasts and osteoblasts. The Binding of Sema4D to its receptor Plexin-B1 in osteoblasts resulted in the activation of the small GTPase RhoA, which inhibits bone formation by suppressing insulin-like growth factor-1 IGF-1 signaling and by modulating osteoblast motility.
Notably, the suppression of Sema4D using a specific antibody was found to markedly prevent bone loss in a model of postmenopausal osteoporosis Table 2 [ 91 ]. This finding identifies a new link between osteoclasts and osteoblast signaling, and suggests that suppression of the Sema4D-Plexin-B1-RhoA signaling axis may provide a new therapeutic target for reducing bone loss and development of bone-increasing drugs.
Several lines of evidence have established that the cells that remodel the skeleton under physiological conditions are the same cells that mediate these processes in pathologic states. Mature bone consists of: an organic matrix osteoid composed mainly of type 1 collagen formed by osteoblasts; a mineral phase which contains the bulk of the body's reserve of calcium and phosphorus in crystalline form hydroxyapatite and deposited in close relation to the collagen fibers; bone cells; and a blood supply with sufficient levels of calcium and phosphate to mineralize the osteoid matrix.
Bone turnover and remodeling occurs throughout life and involves the two-coupled processes of bone formation by osteoblasts and bone resorption by osteoclasts and perhaps osteolytic osteocytes.
Abnormalities of bone remodeling can produce a variety of skeletal disorders Table 3. The metabolic bone diseases may reflect disturbances in the organic matrix, the mineral phase, the cellular processes of remodeling, and the endocrine, nutritional, and other factors that regulate skeletal and mineral homeostasis. These disorders may be hereditary or acquired and usually affect the entire bony skeleton.
Osteoporosis is a common disease of bone remodeling characterized by low bone mass and defects in the microarchitecture of bone tissue; it causes bone fragility and an increased vulnerability to fractures. The loss of bone mass and strength can be contributed to by a failure to reach an optimal peak bone mass as a young adult, b excessive resorption of bone after peak mass has been achieved, or c an impaired bone formation response during remodeling.
Osteoporosis, is traditionally classified into primary and secondary types. Primary osteoporosis is the most common metabolic disorder of the skeleton and has been divided into two subtypes: type I osteoporosis and type II osteoporosis, on the basis of possible differences in etiology. Type I osteoporosis or postmenopausal osteoporosis is a common bone disorder in postmenopausal women and is caused primarily by estrogen deficiency resulting from menopause, whereas type II osteoporosis or age-related osteoporosis is associated primarily with aging in both women and men Table 3.
In contrast, secondary osteoporosis refers to bone disorders that are secondary complications of various other medical conditions, consequences of changes in physical activity, or adverse results of therapeutic interventions for certain disorders [ 92 ]. Postmenopausal osteoporosis is a common disease with a spectrum ranging from asymptomatic bone loss to disabling hip fracture Table 3. The pathogenesis of postmenopausal osteoporosis is caused primarily by the decline in estrogen levels associated with menopause [ 93 ].
Since the establishment of a central role for estrogen deficiency in the pathogenesis of postmenopausal osteoporosis, enormous effort has been focused on elucidating the mechanisms by which estrogens exert their bone-sparing effects. Specifically, estrogen stimulates the expression of OPG in mouse osteoblasts and stromal cells [ 94 ]. Moreover, the expression of RANKL was elevated on the surface of bone marrow cells, such as osteoblasts and lymphocytes, from postmenopausal women with osteoporosis compared with cells from premenopausal controls [ 94 ]; this finding indicates that RANKL plays an important role in the pathogenesis of postmenopausal osteoporosis.
As the global population ages, the prevalence of age-related osteoporosis e. Recent studies indicate that significant trabecular bone loss begins as early as the twenties in men and women long before any major hormonal changes [ 95 ]. It also plays an important role in maintaining plasma calcium homeostasis. The regulation of bone remodeling is both systemic and local. The major systemic regulators include parathyroid hormone PTH , calcitriol, and other hormones such as growth hormone, glucocorticoids, thyroid hormones, and sex hormones.
Hip fractures are especially troublesome as they result in a long recovery period during which complications that may lead to death are quite common. Role of Growth Factors Recent research has suggested that certain growth factors may work to locally alter bone formation by increasing osteoblast activity. Insulin-like growth factors protect cartilage cells, and are associated with the activation of osteocytes. The transforming growth factor beta superfamily includes bone morphogenic proteins involved in osteogenesis.
Fibroblast growth factor activates various cells of the bone marrow including osteoclasts and osteoblasts. Platelet-derived growth factor has been found to enhance bone collagen degradation.
Clinical Note Osteoporosis means porous bone, which is caused by an over-reaction to osteoclastic bone resorption, and makes bones quite fragile for the elderly. Key Points Bone remodeling involves resorption by osteoclasts and replacement by osteoblasts. Osteoblasts and osteoclasts are referred to as bone remodeling units. The purpose of bone remodeling is to regulate calcium homeostasis, repair micro-damage to bones from everyday stress, and to shape the skeleton during growth.
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