Osteoporosis pathophysiology: Difference between revisions
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The pathophysiology of [[osteoporosis]] basically involves an imbalance between bone resorption and bone formation. Major factors that contribute to the development of [[osteoporosis]] include: estrogen deficit, and aging. The main pathway, through which these factors might lead to osteoporosis is [[Reactive oxygen species|reactive oxygen species (ROS)]] damage to [[osteocytes]]. Decreasing the capability of [[autophagy]] in [[osteocytes]] is another important issue; which make them vulnerable to [[oxidative]] stresses. | The pathophysiology of [[osteoporosis]] basically involves an imbalance between bone resorption and bone formation. Major factors that contribute to the development of [[osteoporosis]] include: estrogen deficit, and aging. The main pathway, through which these factors might lead to osteoporosis is [[Reactive oxygen species|reactive oxygen species (ROS)]] damage to [[osteocytes]]. Decreasing the capability of [[autophagy]] in [[osteocytes]] is another important issue; which make them vulnerable to [[oxidative]] stresses. | ||
== | ==Pathogenesis== | ||
In normal [[bone]], there is constant remodeling of [[bone]] [[matrix (biology)|matrix]]. Up to 10% of all [[bone mass]] may be undergoing remodeling at any point of the time. The process takes place in [[bone]] [[multicellular]] units (BMUs) as first described by Frost, in 1963. [[Osteoporosis]] is a [[disease]] could involve all [[bones]] of human body, majorly defined as [[Bone loss|mass loss]] and also micro-architectural deterioration in [[bones]]. The final destination in [[osteoporosis]] is [[Bone fracture|fracture]], causing by the predefined mechanisms.<ref>Frost HM, Thomas CC. Bone Remodeling Dynamics. Springfield, IL: 1963.</ref><ref name="pmid26491648">{{cite journal| author=Pagliari D, Ciro Tamburrelli F, Zirio G, Newton EE, Cianci R| title=The role of "bone immunological niche" for a new pathogenetic paradigm of osteoporosis. | journal=Anal Cell Pathol (Amst) | year= 2015 | volume= 2015 | issue= | pages= 434389 | pmid=26491648 | doi=10.1155/2015/434389 | pmc=4605147 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26491648 }} </ref> | |||
The main mechanism, through which [[bone mass]] would be lost, is activation of osteoclastogenic pathway; there are two main cells involved in, include [[osteoblasts]] and [[osteoclasts]]. [[Bone]] is reabsorbed by [[osteoclast]]<nowiki/>s, after which new [[bone]] is deposited by [[osteoblast|osteoblasts]].The main predictor of final result, rearrangement or loss of [[bone]] tissue, are [[osteoclasts]].<ref name="pmid26491648" /><ref name="Raisz">{{cite journal | author = Raisz L | title = Pathogenesis of osteoporosis: concepts, conflicts, and prospects. | journal = J Clin Invest| volume = 115 | issue = 12 | pages = 3318-25 | year = 2005 | id = PMID 16322775 |url=http://www.jci.org/cgi/content/full/115/12/3318 | doi=10.1172/JCI27071}}</ref> | |||
Normal balance between [[osteoblasts]] and [[osteoclasts]] activities, resulted from tissue micro-environment (affected by [[macrophages]] and [[Innate immune system|innate adaptive immunity]]), may lead to functional [[bone]] [[homeostasis]]; finally, forming normal [[bone]]. Whenever, the balance or its predictor factors become disturbed, it may lead to increasing the [[Osteoclast|osteoclastic]] activity compare with [[Osteoblast|osteoblastic]] activity; destruction move above construction, and [[Bone loss|bone mass loss]] is happened.<ref name="pmid26491648" /> | |||
In addition to [[estrogen]], [[calcium metabolism]] plays a significant role in [[bone]] turnover. Deficiency of [[calcium in biology|calcium]] and [[vitamin D]] leads to impaired [[bone]] deposition. The [[parathyroid gland]]s react to low [[calcium]] levels by secreting [[parathyroid hormone]] ([[Parathyroid hormone|parathormone]], [[Parathyroid hormone|PTH]]), which increases [[bone]] resorption; ensuring to maintain sufficient [[calcium]] level in the [[blood]].<ref name="pmid21182397">{{cite journal| author=Fleet JC, Schoch RD| title=Molecular mechanisms for regulation of intestinal calcium absorption by vitamin D and other factors. | journal=Crit Rev Clin Lab Sci | year= 2010 | volume= 47 | issue= 4 | pages= 181-95 | pmid=21182397 | doi=10.3109/10408363.2010.536429 | pmc=3235806 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21182397 }} </ref> | |||
The role of [[calcitonin]], a [[hormone]] produced by the [[thyroid]] that increases [[bone]] deposition, is less clear and probably less significant.<ref name="Raisz" /> | |||
== Genetics == | |||
[[Genes]] involved in the [[pathogenesis]] of [[osteoporosis]] are about 15 [[genes]] that majorly can categorized in three main groups, include the [[Estrogen receptor|estrogen receptor (ESR)]] related genes, receptor activator of nuclear factor kappa-B (RANK) related [[genes]], and Lipoprotein receptor-related protein 5 (LRP5) related genes. | |||
=== Lipoprotein receptor-related protein 5 (LRP5) === | |||
LPR5 and LPR6 are both transmembrane receptors. Actually, they are co-receptors for canonical Wnt signaling pathway. Wnt pathway is a critical pathway in developing various organs,such as extremities, central nervous system (CNS), and also differentiation of osteoblasts and chondrocytes. The downstream protein after Wnt/LPR5/LPR6 activation is β-cathenin. Some extracellular proteins like Dickkopf (Dkk) could bind to LPR5 and LPR6, decreasing and inhibiting the Wnt signaling pathway. | |||
=== Transforming growth factor (TGF)-β1 === | |||
* [[Osteoprotegerin | The major family of TGF-β have important roles in cell differentiating and also other functions before and after birth. But the most important member of the family in bone and fibrous tissues is TGF-β1, encoding by ''TGF-β1'' gene. It can play a main role in determining osteoporosis susceptibility. In case the TGF-β gene become inactivated, it may result in major inflammations and also severe osteoporosis. | ||
=== Bone morphogenic proteins (BMPs) === | |||
BMPs are also members of the superfamily of TGF-β proteins. The main role of BMP is some modulation of bone mineral density along with limited roles in limb differentiation. The various changes in different codon location among the gene sequence has been proved to cause osteoporosis in patients. | |||
=== Sclerostin === | |||
Sclerostin is a protein with cysteine contained knots in its structure, share some homologous sequences with anti BMP proteins. ''SOST'' gene has major role in BMD regulations, while the patient with heterozygous mutation may be asymptomatic but would have higher BMD. In some studies, it has found that ''SOST may cause reduction in bone mass; over expression of the gene is contributed to reduced bone formation and decreased BMD. The decrease in BMD following'' SOST ''over expression may be due to inhibitory effects of'' sclerostin ''on Wnt signaling pathway, through binding and interacting LPR5 and LPR6 proteins.'' | |||
=== CBFA1 === | |||
* [[Osteoprotegerin|Osteoprotegerin (OPG)]] binds [[RANKL]] before it has an opportunity to bind to [[RANK]]; hence, suppresses its ability to increase [[bone]] resorption. [[RANKL]], [[RANK]], and [[Osteoprotegerin|OPG]] are closely related to [[Tumor necrosis factor|tumor necrosis factor (TNF)]] and its [[Receptor (biochemistry)|receptors]]. The role of the [[Wnt signaling pathway|''wnt'' signalling pathway]] is recognized, but less well understood. | |||
== Associated conditions == | |||
== Gross pathology == | |||
* On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. | |||
* | |||
== Microscopic pathology == | |||
On [[microscopic]] [[histopathological]] analysis, increased activity of [[osteoclasts]] and decreased activity of [[osteoblasts]] are characteristic findings of [[osteoporosis]]. | |||
Manolagas in 2010, suggested that main [[pathogenesis]] of [[osteoporosis]] shifted from [[estrogen]]-based theory to age-related issue. The theory is consisted of [[Reactive oxygen species|reactive oxygen species (ROS)]] as main role. He mentioned that loss of [[estrogen]] and [[androgen]] in body would make [[bone]] tissue more vulnerable to [[Reactive oxygen species|ROS]], make the [[osteocytes]] prone to deterioration.<ref name="pmid20051526">{{cite journal |vauthors=Manolagas SC |title=From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis |journal=Endocr. Rev. |volume=31 |issue=3 |pages=266–300 |year=2010 |pmid=20051526 |pmc=3365845 |doi=10.1210/er.2009-0024 |url=}}</ref> | |||
When [[Reactive oxygen species|ROS]] become elevated in [[bone]] tissue, several factors would be increased include T and B [[lymphocytes]], nuclear factor kappa-B (NF-kB), and also osteoclastogenic [[cytokines]] (e.g., [[IL-1]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], and [[RANKL|receptor activator of NF-kB ligand (RANKL)]]). On the other hand, [[androgen]] may decrease all of them.<ref name="pmid16670759">{{cite journal |vauthors=Weitzmann MN, Pacifici R |title=Estrogen deficiency and bone loss: an inflammatory tale |journal=J. Clin. Invest. |volume=116 |issue=5 |pages=1186–94 |year=2006 |pmid=16670759 |pmc=1451218 |doi=10.1172/JCI28550 |url=}}</ref> | |||
[[RANKL]] is thought to be the most important factor need for formation of [[osteoclasts]]; however, Xiong has challenged the old assumption and found that [[osteoblast]] and its [[Progenitor cell|progenitor cells]] are not the main source of [[RANKL]], essential for [[osteoclast]] formation and remodeling in adult bones. The main role of [[matrix]] resorption belongs to the cells embedded in itself.<ref name="pmid21909103">{{cite journal |vauthors=Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA |title=Matrix-embedded cells control osteoclast formation |journal=Nat. Med. |volume=17 |issue=10 |pages=1235–41 |year=2011 |pmid=21909103 |pmc=3192296 |doi=10.1038/nm.2448 |url=}}</ref> | |||
[[Autophagy]] is the mechanism, through which [[osteocytes]] use to run away from [[Oxidative stress|oxidative stresses]]. The capability of [[autophagy]] in cells decrease as they aged; or better to say, it is one of the reasons of aging, indeed. As the [[osteocytes]] grow, they lose their viability more; make the [[bone]] holes bigger and [[bone]] mass lower.<ref name="pmid23645674">{{cite journal |vauthors=Onal M, Piemontese M, Xiong J, Wang Y, Han L, Ye S, Komatsu M, Selig M, Weinstein RS, Zhao H, Jilka RL, Almeida M, Manolagas SC, O'Brien CA |title=Suppression of autophagy in osteocytes mimics skeletal aging |journal=J. Biol. Chem. |volume=288 |issue=24 |pages=17432–40 |year=2013 |pmid=23645674 |pmc=3682543 |doi=10.1074/jbc.M112.444190 |url=}}</ref><nowiki/><nowiki/> | |||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Raviteja Guddeti, M.B.B.S.[3]
Overview
The pathophysiology of osteoporosis basically involves an imbalance between bone resorption and bone formation. Major factors that contribute to the development of osteoporosis include: estrogen deficit, and aging. The main pathway, through which these factors might lead to osteoporosis is reactive oxygen species (ROS) damage to osteocytes. Decreasing the capability of autophagy in osteocytes is another important issue; which make them vulnerable to oxidative stresses.
Pathogenesis
In normal bone, there is constant remodeling of bone matrix. Up to 10% of all bone mass may be undergoing remodeling at any point of the time. The process takes place in bone multicellular units (BMUs) as first described by Frost, in 1963. Osteoporosis is a disease could involve all bones of human body, majorly defined as mass loss and also micro-architectural deterioration in bones. The final destination in osteoporosis is fracture, causing by the predefined mechanisms.[1][2]
The main mechanism, through which bone mass would be lost, is activation of osteoclastogenic pathway; there are two main cells involved in, include osteoblasts and osteoclasts. Bone is reabsorbed by osteoclasts, after which new bone is deposited by osteoblasts.The main predictor of final result, rearrangement or loss of bone tissue, are osteoclasts.[2][3]
Normal balance between osteoblasts and osteoclasts activities, resulted from tissue micro-environment (affected by macrophages and innate adaptive immunity), may lead to functional bone homeostasis; finally, forming normal bone. Whenever, the balance or its predictor factors become disturbed, it may lead to increasing the osteoclastic activity compare with osteoblastic activity; destruction move above construction, and bone mass loss is happened.[2]
In addition to estrogen, calcium metabolism plays a significant role in bone turnover. Deficiency of calcium and vitamin D leads to impaired bone deposition. The parathyroid glands react to low calcium levels by secreting parathyroid hormone (parathormone, PTH), which increases bone resorption; ensuring to maintain sufficient calcium level in the blood.[4]
The role of calcitonin, a hormone produced by the thyroid that increases bone deposition, is less clear and probably less significant.[3]
Genetics
Genes involved in the pathogenesis of osteoporosis are about 15 genes that majorly can categorized in three main groups, include the estrogen receptor (ESR) related genes, receptor activator of nuclear factor kappa-B (RANK) related genes, and Lipoprotein receptor-related protein 5 (LRP5) related genes.
LPR5 and LPR6 are both transmembrane receptors. Actually, they are co-receptors for canonical Wnt signaling pathway. Wnt pathway is a critical pathway in developing various organs,such as extremities, central nervous system (CNS), and also differentiation of osteoblasts and chondrocytes. The downstream protein after Wnt/LPR5/LPR6 activation is β-cathenin. Some extracellular proteins like Dickkopf (Dkk) could bind to LPR5 and LPR6, decreasing and inhibiting the Wnt signaling pathway.
Transforming growth factor (TGF)-β1
The major family of TGF-β have important roles in cell differentiating and also other functions before and after birth. But the most important member of the family in bone and fibrous tissues is TGF-β1, encoding by TGF-β1 gene. It can play a main role in determining osteoporosis susceptibility. In case the TGF-β gene become inactivated, it may result in major inflammations and also severe osteoporosis.
Bone morphogenic proteins (BMPs)
BMPs are also members of the superfamily of TGF-β proteins. The main role of BMP is some modulation of bone mineral density along with limited roles in limb differentiation. The various changes in different codon location among the gene sequence has been proved to cause osteoporosis in patients.
Sclerostin
Sclerostin is a protein with cysteine contained knots in its structure, share some homologous sequences with anti BMP proteins. SOST gene has major role in BMD regulations, while the patient with heterozygous mutation may be asymptomatic but would have higher BMD. In some studies, it has found that SOST may cause reduction in bone mass; over expression of the gene is contributed to reduced bone formation and decreased BMD. The decrease in BMD following SOST over expression may be due to inhibitory effects of sclerostin on Wnt signaling pathway, through binding and interacting LPR5 and LPR6 proteins.
CBFA1
- Osteoprotegerin (OPG) binds RANKL before it has an opportunity to bind to RANK; hence, suppresses its ability to increase bone resorption. RANKL, RANK, and OPG are closely related to tumor necrosis factor (TNF) and its receptors. The role of the wnt signalling pathway is recognized, but less well understood.
Associated conditions
Gross pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic pathology
On microscopic histopathological analysis, increased activity of osteoclasts and decreased activity of osteoblasts are characteristic findings of osteoporosis.
Manolagas in 2010, suggested that main pathogenesis of osteoporosis shifted from estrogen-based theory to age-related issue. The theory is consisted of reactive oxygen species (ROS) as main role. He mentioned that loss of estrogen and androgen in body would make bone tissue more vulnerable to ROS, make the osteocytes prone to deterioration.[5]
When ROS become elevated in bone tissue, several factors would be increased include T and B lymphocytes, nuclear factor kappa-B (NF-kB), and also osteoclastogenic cytokines (e.g., IL-1, IL-6, IL-7, and receptor activator of NF-kB ligand (RANKL)). On the other hand, androgen may decrease all of them.[6]
RANKL is thought to be the most important factor need for formation of osteoclasts; however, Xiong has challenged the old assumption and found that osteoblast and its progenitor cells are not the main source of RANKL, essential for osteoclast formation and remodeling in adult bones. The main role of matrix resorption belongs to the cells embedded in itself.[7]
Autophagy is the mechanism, through which osteocytes use to run away from oxidative stresses. The capability of autophagy in cells decrease as they aged; or better to say, it is one of the reasons of aging, indeed. As the osteocytes grow, they lose their viability more; make the bone holes bigger and bone mass lower.[8]
References
- ↑ Frost HM, Thomas CC. Bone Remodeling Dynamics. Springfield, IL: 1963.
- ↑ 2.0 2.1 2.2 Pagliari D, Ciro Tamburrelli F, Zirio G, Newton EE, Cianci R (2015). "The role of "bone immunological niche" for a new pathogenetic paradigm of osteoporosis". Anal Cell Pathol (Amst). 2015: 434389. doi:10.1155/2015/434389. PMC 4605147. PMID 26491648.
- ↑ 3.0 3.1 Raisz L (2005). "Pathogenesis of osteoporosis: concepts, conflicts, and prospects". J Clin Invest. 115 (12): 3318–25. doi:10.1172/JCI27071. PMID 16322775.
- ↑ Fleet JC, Schoch RD (2010). "Molecular mechanisms for regulation of intestinal calcium absorption by vitamin D and other factors". Crit Rev Clin Lab Sci. 47 (4): 181–95. doi:10.3109/10408363.2010.536429. PMC 3235806. PMID 21182397.
- ↑ Manolagas SC (2010). "From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis". Endocr. Rev. 31 (3): 266–300. doi:10.1210/er.2009-0024. PMC 3365845. PMID 20051526.
- ↑ Weitzmann MN, Pacifici R (2006). "Estrogen deficiency and bone loss: an inflammatory tale". J. Clin. Invest. 116 (5): 1186–94. doi:10.1172/JCI28550. PMC 1451218. PMID 16670759.
- ↑ Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O'Brien CA (2011). "Matrix-embedded cells control osteoclast formation". Nat. Med. 17 (10): 1235–41. doi:10.1038/nm.2448. PMC 3192296. PMID 21909103.
- ↑ Onal M, Piemontese M, Xiong J, Wang Y, Han L, Ye S, Komatsu M, Selig M, Weinstein RS, Zhao H, Jilka RL, Almeida M, Manolagas SC, O'Brien CA (2013). "Suppression of autophagy in osteocytes mimics skeletal aging". J. Biol. Chem. 288 (24): 17432–40. doi:10.1074/jbc.M112.444190. PMC 3682543. PMID 23645674.