It was proposed that the coupling molecules were stored in the bone matrix and liberated during bone resorption. Collagen type I is the primary organic component of bone and accumulation contributes, in part, to the cessation of cell growth. When proliferation ceases, proteins associated with bone cell phenotype are detected, e.
For bone to assume its final form, hydroxylapatite is incorporated into this newly deposited osteoid [ 47 , 49 ]. With the onset of mineralization, several other bone expressed genes are induced to maximal levels bone sialoprotein, osteopontin and osteocalcin [ 32 , 47 ]. When an equal quantity of resorbed bone has been replaced, the remodeling cycle concludes Figure 2. Termination Phase- The termination signals are largely unknown, and include the terminal differentiation of the osteoblast. The role of osteocytes is emerging [ 12 , 32 ].
The cells then gradually flatten as they slow production, and finally they become quiescent lining cells. Some of the osteoblast differentiate into osteocytes and remain in the matrix [ 12 ]. The osteocytes may secrete inhibitory factors that slow the rate of bone formation as the resorbed cavity is nearly filled.
Bone remodeling is mediated by a balance of osteoblast and osteoclast cell activity, which together, maintain bone mass and mineral homeostasis. Both decreased bone formation and increased bone resorption may result in bone loss. Therefore, the stimulation of bone formation may be another important factor for the prevention and treatment of bone loss Figure 2.
The process of bone remodeling is essential for adult bone homeostasis. This control involves a complex mechanism compound by numerous local and systemic factors, and their expression and release is controlled finely. The main factor that affects normal bone remodeling is the regulation of osteoblasts and osteoclasts. Local and systemic factors can affect bone remodeling by directly or indirectly targeting mature cells and their respective progenitor cells.
The metabolic functions of the bone are mediated by two major calcium-regulating hormones, parathyroid hormone PTH and 1,dihydroxy vitamin D Table 1 [ 50 ]. Estrogen decreases bone formation by decreasing remodeling, but formation is decreased less than resorption and bone mass increases. Data and modified from Raisz, L. 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.
Mickey Mouse Sign in Paget's Disease. Paget's Disease of the Mandible. Lincoln Sign on Bone Scintigraphy. Clin Nucl Med. Weissman, Barbara N.
Imaging of Arthritis and Metabolic Bone Disease. Related articles: Metabolic bone disease. Promoted articles advertising.
Figure 1: histopathology Figure 1: histopathology. Case 2 Case 2. Case 3: skull Case 3: skull. Case 4: pelvis Case 4: pelvis. Case 5: distal femur Case 5: distal femur.
Case 6: scapula Case 6: scapula. Case 7: skull Case 7: skull. Case 8: with secondary osteosarcoma Case 8: with secondary osteosarcoma. Case 9 Case 9. Case 11 Case Case involving sternum Case involving sternum. Case 14 Case Case rib Case rib. Case 16 Case Case 17 Case Case polyostotic involvement Case polyostotic involvement.
Case 19 Case Case 20 Case Case 21 Case Case with blade of grass sign Case with blade of grass sign. Case affecting femur Case affecting femur.
Case right iliac bone Case right iliac bone. Case 26 Case Case pathological fractures Case pathological fractures. Case 28 Case Case thumb Case thumb. Case sternal Paget disease Case sternal Paget disease. Hyperostosis frontalis interna Hyperostosis frontalis interna.
Fibrous dysplasia Fibrous dysplasia. Thalassemia major - calvarial changes Thalassemia major - calvarial changes. Many major nerves in the body run through or alongside the bones, so abnormal bone growth might cause a bone to compress, pinch, or damage a nerve, triggering pain. According to the American College of Rheumatology, more than one family member has the disorder in 30 percent of cases.
Another suggestion is that the disorder possibly occurs due to infection by the measles virus during childhood. People with the disorder have an excess of alkaline phosphatase, an enzyme, in the blood.
However, many other diseases or conditions might be the cause of elevated alkaline phosphatase levels. Bone scans can reveal abnormalities of bone remodeling, including areas of increased and decreased bone deposition. The might also prescribe vitamin D and calcium as supplements.
Bisphosphonates are medications that help reduce the breakdown of disordered bone. People receiving bisphosphonates also need to maintain adequate levels of vitamin D and calcium. The Office of Dietary Supplements ODS recommends that people should consume 1, miligrams mg of calcium and at least International Units IU of vitamin D a day between the ages of 51 and 70 years.
Take oral bisphosphonates and calcium supplements at least 2 hours apart, as calcium can reduce the absorption of bisphosphonate. Bisphosphonates and calcium can protect the weaker parts of bone that cause deformity and are at high risk of fracture.
Treatment of these fractures usually involves an intramedullary rod. An orthopedic surgeon inserts this through the marrow cavity in the center of the bone. In this procedure, the surgeon removes a wedge of bone to correct a poorly aligned bone.
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