Osteoporosis pathophysiology: Difference between revisions
Jump to navigation
Jump to search
Iqra Qamar (talk | contribs) |
m (Bot: Removing from Primary care) |
||
| (20 intermediate revisions by 6 users not shown) | |||
| Line 1: | Line 1: | ||
__NOTOC__ | __NOTOC__ | ||
{{Osteoporosis}} | {{Osteoporosis}} | ||
{{CMG}}; {{AE}}{{EG}} | {{CMG}}; {{AE}} {{EG}} | ||
==Overview== | ==Overview== | ||
The [[pathophysiology]] of osteoporosis | The [[pathophysiology]] of osteoporosis consists of an imbalance between [[bone]] resorption and [[bone]] formation. Major factors contributing to the development of osteoporosis include [[estrogen]] deficit and [[aging]]. The main mechanism, by which these factors might lead to osteoporosis is [[Reactive oxygen species|reactive oxygen species (ROS)]] induced damage to [[osteocytes]]. Decreased capability of [[osteocyte]] [[autophagy]] is another important issue; which makes them vulnerable to [[oxidative]] stresses. [[Genes]] involved in the [[pathogenesis]] of osteoporosis can be categorized into four main groups namely, [[osteoblast]] regulatory [[genes]], [[osteoclast]] regulatory [[genes]], [[bone matrix]] elements [[genes]], and [[hormone]]/[[receptor]] [[genes]]. | ||
==Pathogenesis== | ==Pathophysiology== | ||
* In normal [[bone]], there is constant remodeling of [[bone]] [[matrix (biology)|matrix]] | [[Osteoporosis]] is mainly defined as [[Bone loss| bone mass loss]] and micro-architectural deterioration in [[bones]]. The final outcome of [[osteoporosis]] is [[Bone fracture|fracture]]. | ||
* The | |||
* Normal balance between [[ | === Pathogenesis === | ||
* 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]]) | * In normal [[bone]], there is constant remodeling of [[bone]] [[matrix (biology)|matrix]]. The process takes place in [[bone]] [[multicellular]] units (BMUs).<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 process through which loss of [[bone mass]] occurs is the activation of osteoclastogenic pathway. | |||
=== Osteoclastogenic pathway === | |||
* The two main [[cells]] involved in osteoclastogenic pathway are [[osteoblasts]] and [[osteoclasts]]. | |||
* [[Bone]] resorption is caused by [[osteoclast]]<nowiki/>s, after which new [[bone]] is deposited by [[osteoblast|osteoblasts]]. | |||
* Osteoclasts determine the final outcome of bone resorption.<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 [[osteoblast]] and [[osteoclast]] activities within a bone is influenced by [[macrophages]] and [[Innate immune system|innate adaptive immunity]]. This leads to the formation of a normal bone. | |||
* Whenever there is a disturbance of this balance leading to increased [[Osteoclast|osteoclastic]] activity relative to [[Osteoblast|osteoblastic]] activity, the result is resorption, and eventual [[Bone loss|bone mass loss]].<ref name="pmid26491648" /> | |||
=== Role of Hormones === | |||
* In addition to [[estrogen]], [[calcium metabolism|calcium]] 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 [[Secretion|secreting]] [[parathyroid hormone]] ([[Parathyroid hormone|parathormone]], [[Parathyroid hormone|PTH]]) increasing [[bone]] resorption in a bid to ensure adequate calcium levels 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" /> | * The role of [[calcitonin]], a [[hormone]] produced by the [[thyroid]] that increases [[bone]] deposition, is less clear and probably less significant.<ref name="Raisz" /> | ||
=== Manolagas Theory === | |||
* Manolagas in 2010, suggested that main [[pathogenesis]] of [[osteoporosis]] shifted from [[estrogen]]-based theory to age-related issue. | |||
* The theory consists of [[Reactive oxygen species|reactive oxygen species (ROS)]] as the main factor involved in the osteoporosis. | |||
* According to Manolagas theory, loss of [[estrogen]] and [[androgen]] in the body would make [[bone]] tissue more vulnerable to [[Reactive oxygen species|ROS]], making 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 needed for formation of [[osteoclasts]]. | |||
=== Xiong Theory === | |||
* Xiong proposed that [[osteoblast]] and its [[Progenitor cell|progenitor cells]] are not the main sources of [[RANKL]] essential for [[osteoclast]] formation and remodeling in adult bones. | |||
* [[Osteoprotegerin|Osteoprotegerin (OPG)]] binds [[RANKL]] before it has an opportunity to bind to [[RANK]] thereby suppressing 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'' signaling pathway]] is recognized, but not clearly understood. | |||
== Genetics == | == Genetics == | ||
[[Genes]] involved in the [[pathogenesis]] of [[osteoporosis]] can be categorized into four main groups: | [[Genes]] involved in the [[pathogenesis]] of [[osteoporosis]] can be categorized into four main groups. Mutation in any of these genes can lead to the development of some rare diseases. These genes include: | ||
* [[Osteoblast]] regulatory [[genes]] | |||
{| | * [[Osteoclast]] regulatory [[genes]] | ||
* [[Bone matrix]] elements genes | |||
* [[Hormone]]/[[receptor]] [[genes]]. | |||
{| cellpadding="2" border="1" align="center" | |||
|- style="background:Gainsboro; color:black" | |- style="background:Gainsboro; color:black" | ||
! Group | ! Group | ||
| Line 73: | Line 103: | ||
=== Lipoprotein receptor-related protein 5 (LRP5) === | === Lipoprotein receptor-related protein 5 (LRP5) === | ||
* [[Wnt signaling pathway|Wnt pathway]] is a critical pathway in developing various organs, such as [[extremities]], [[Central nervous system|central nervous system (CNS)]], [[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]]. | |||
* OPPG is [[osteoporosis]] along with [[blindness]] due to [[vitreous]] [[opacity]] while HBM is an abnormal increase of [[Bone mineral density|bone mineral density (BMD)]].<ref name="pmid15476573">{{cite journal |vauthors=Johnson ML, Harnish K, Nusse R, Van Hul W |title=LRP5 and Wnt signaling: a union made for bone |journal=J. Bone Miner. Res. |volume=19 |issue=11 |pages=1749–57 |year=2004 |pmid=15476573 |doi=10.1359/JBMR.040816 |url=}}</ref><ref name="pmid8659519">{{cite journal| author=Gong Y, Vikkula M, Boon L, Liu J, Beighton P, Ramesar R et al.| title=Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. | journal=Am J Hum Genet | year= 1996 | volume= 59 | issue= 1 | pages= 146-51 | pmid=8659519 | doi= | pmc=1915094 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8659519 }}</ref><ref name="pmid9199553">{{cite journal |vauthors=Johnson ML, Gong G, Kimberling W, Reckér SM, Kimmel DB, Recker RB |title=Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13) |journal=Am. J. Hum. Genet. |volume=60 |issue=6 |pages=1326–32 |year=1997 |pmid=9199553 |pmc=1716125 |doi= |url=}}</ref> | |||
=== Transforming growth factor (TGF)-β1 === | === Transforming growth factor (TGF)-β1 === | ||
The major family of [[TGF-β]] | * The major family of [[TGF-β]] plays an important role in cell [[differentiation]] before and after [[birth]]. | ||
* The most important member of the family in [[bone]] and [[fibrous]] tissues is [[TGF-β|TGF-β1]], encoded by ''[[TGF-β|TGF-β1]]'' [[gene]]. | |||
* [[TGF-β|TGF-β1]] plays the main role in determining [[osteoporosis]] susceptibility. | |||
* If [[TGF-β]] gene becomes inactivated, it may result in major [[inflammation]] and severe [[osteoporosis]]. | |||
* [[polymorphism|Polymorphisms]] within the [[intron]] 4 of the [[TGF-β|TGF''-β1'' gene]] has been shown to be the main cause of severe [[osteoporosis]]. | |||
* Mutations in [[TGF-β|TGF''-β1'']] [[gene]] causes [[Camurati-Engelmann disease|Camurati-Engelmann (CED) disease]], which is a rare [[disease]] of [[hyperostosis]] and [[sclerosis]] of [[long bones]] [[metaphysis]].<ref name="pmid9701466">{{cite journal |vauthors=Geiser AG, Zeng QQ, Sato M, Helvering LM, Hirano T, Turner CH |title=Decreased bone mass and bone elasticity in mice lacking the transforming growth factor-beta1 gene |journal=Bone |volume=23 |issue=2 |pages=87–93 |year=1998 |pmid=9701466 |doi= |url=}}</ref><ref name="pmid10973241">{{cite journal |vauthors=Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, Yamada K, Kondo S, Ikegawa S, Nishimura G, Fukushima Y, Nakagomi T, Saito H, Sugimoto T, Kamegaya M, Hisa K, Murray JC, Taniguchi N, Niikawa N, Yoshiura K |title=Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease |journal=Nat. Genet. |volume=26 |issue=1 |pages=19–20 |year=2000 |pmid=10973241 |doi=10.1038/79128 |url=}}</ref> | |||
=== Bone morphogenic proteins (BMPs) === | === Bone morphogenic proteins (BMPs) === | ||
BMPs are also members of the superfamily of [[TGF-β]] [[proteins]]. | * BMPs are also members of the superfamily of [[TGF-β]] [[proteins]]. | ||
* Various changes in different [[codon]] location among the [[gene]] [[Sequence (biology)|sequence]] have been proved to cause low [[Bone mineral density|bone mineral density (BMD)]] and also [[osteoporosis]] in patients.<ref name="pmid16127465">{{cite journal |vauthors=Seemann P, Schwappacher R, Kjaer KW, Krakow D, Lehmann K, Dawson K, Stricker S, Pohl J, Plöger F, Staub E, Nickel J, Sebald W, Knaus P, Mundlos S |title=Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2 |journal=J. Clin. Invest. |volume=115 |issue=9 |pages=2373–81 |year=2005 |pmid=16127465 |pmc=1190374 |doi=10.1172/JCI25118 |url=}}</ref> | |||
=== Sclerostin === | === Sclerostin === | ||
[[Sclerostin]] is a [[protein]] with [[cysteine]] contained knots in its structure | * [[Sclerostin]] is a [[protein]] with [[cysteine]] contained knots in its structure that share some homologous [[Sequence (biology)|sequences]] with anti-BMP [[proteins]]. | ||
* [[SOST|SOST gene]] has a major role in [[Bone mineral density|BMD]] regulations, while the patient with [[heterozygous]] [[mutation]] may be [[asymptomatic]] they usually have higher [[Bone mineral density|BMD]]. | |||
* Decrease in [[Bone mineral density|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. | |||
* The [[mutations]] in the [[SOST]] [[gene]] may lead to van Buchem and [[Sclerosteosis|Sclerosteosis bone dysplasias]]. These [[diseases]] are mainly severe [[osteosclerosis]] of [[skull]], [[mandible]], or any other [[Trabecular bone|trabecular bones]]. | |||
* [[Sclerosteosis]] is more severe than van Buchem [[disease]] and mainly involves the [[upper extremity]] [[bones]].<ref name="van BezooijenRoelen2004">{{cite journal|last1=van Bezooijen|first1=Rutger L.|last2=Roelen|first2=Bernard A.J.|last3=Visser|first3=Annemieke|last4=van der Wee-Pals|first4=Lianne|last5=de Wilt|first5=Edwin|last6=Karperien|first6=Marcel|last7=Hamersma|first7=Herman|last8=Papapoulos|first8=Socrates E.|last9=ten Dijke|first9=Peter|last10=Löwik|first10=Clemens W.G.M.|title=Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation, But Not a Classical BMP Antagonist|journal=The Journal of Experimental Medicine|volume=199|issue=6|year=2004|pages=805–814|issn=0022-1007|doi=10.1084/jem.20031454}}</ref><ref name="pmid6323069">{{cite journal |vauthors=Beighton P, Barnard A, Hamersma H, van der Wouden A |title=The syndromic status of sclerosteosis and van Buchem disease |journal=Clin. Genet. |volume=25 |issue=2 |pages=175–81 |year=1984 |pmid=6323069 |doi= |url=}}</ref><ref name="pmid16307387" /> | |||
=== Core binding factor A1 (CBFA1) === | === Core binding factor A1 (CBFA1) === | ||
* CBFA1 is a major [[gene]] in [[bone]] formation. Laboratory animals with a [[mutated]] version or without the [[Wild-type|wild version]] of CBFA1 [[gene]] have failure of development of bone. | |||
* The major role of the [[gene]] is to [[differentiate]] [[osteoblasts]] in order to construct the [[bones]]. | |||
* Lack of the CBFA1 [[gene]] in the human body may lead to [[Cleidocranial dysplasia|cleidocranial dysplasia (CCD)]], a [[disease]] in which patient has [[clavicular]] [[hypoplasia]] or complete [[aplasia]], patent [[Fontanel|fontanels]], [[short stature]], [[teeth]] abnormalities, and other [[skeletal]] deformities.<ref name="pmid9182764">{{cite journal |vauthors=Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ |title=Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development |journal=Cell |volume=89 |issue=5 |pages=765–71 |year=1997 |pmid=9182764 |doi= |url=}}</ref> | |||
=== Cathepsin K === | === Cathepsin K === | ||
* A mutation in [[cathepsin K]] gene may cause [[Pycnodysostosis|Pycnodysostosis syndrome]] that is a rare [[syndrome]] of [[bone]] [[dysplasia]] along with [[osteosclerosis]] and [[short stature]].<ref name="GelbShi1996">{{cite journal|last1=Gelb|first1=B. D.|last2=Shi|first2=G.-P.|last3=Chapman|first3=H. A.|last4=Desnick|first4=R. J.|title=Pycnodysostosis, a Lysosomal Disease Caused by Cathepsin K Deficiency|journal=Science|volume=273|issue=5279|year=1996|pages=1236–1238|issn=0036-8075|doi=10.1126/science.273.5279.1236}}</ref> | |||
=== Vacuolar proton pump a3 subunit (TCIRG1) === | === Vacuolar proton pump a3 subunit (TCIRG1) === | ||
* It seems that this [[gene]] has some role in the regulation of [[Bone mineral density|bone mineral density (BMD)]]. | |||
* The majority of [[recessive]] forms of [[osteopetrosis]] are caused by inactivation of TCIRG1 [[gene]].<ref name="pmid10888887">{{cite journal |vauthors=Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A |title=Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis |journal=Nat. Genet. |volume=25 |issue=3 |pages=343–6 |year=2000 |pmid=10888887 |doi=10.1038/77131 |url=}}</ref> | |||
=== Chloride channel 7 (CLCN7) === | === Chloride channel 7 (CLCN7) === | ||
* It controls the acidification of the environment and facilitate the [[resorption]] of the [[bone]]. | |||
* Inactivation [[mutations]] of the [[gene]] may lead to severe forms of [[osteopetrosis]].<ref name="pmid16307387">{{cite journal |vauthors=Balemans W, Van Wesenbeeck L, Van Hul W |title=A clinical and molecular overview of the human osteopetroses |journal=Calcif. Tissue Int. |volume=77 |issue=5 |pages=263–74 |year=2005 |pmid=16307387 |doi=10.1007/s00223-005-0027-6 |url=}}</ref> | |||
=== Collagen type Iα I === | === Collagen type Iα I === | ||
* [[Type-I collagen|Collagen type 1 gene]] is one of the most important [[gene]]s in [[osteoporosis]] as [[Collagen I|collagen type 1]] is the major conforming element in the [[bones|bones.]] | |||
* [[mutation]] in the [[Type-I collagen|collagen type 1]] [[gene]] may cause [[osteogenesis imperfecta]], in which the [[Bone mineral density|bone mineral density (BMD)]] is increased and the [[bones]] become fragile.<ref name="pmid10024373">{{cite journal |vauthors=Boyde A, Travers R, Glorieux FH, Jones SJ |title=The mineralization density of iliac crest bone from children with osteogenesis imperfecta |journal=Calcif. Tissue Int. |volume=64 |issue=3 |pages=185–90 |year=1999 |pmid=10024373 |doi= |url=}}</ref> | |||
== Associated conditions == | == Associated conditions == | ||
| Line 127: | Line 178: | ||
== Microscopic pathology == | == Microscopic pathology == | ||
* [[Bone]] with osteoporosis shows increased | * [[Bone]] with osteoporosis shows increased number of [[osteoclasts]] and decreased number of [[osteoblasts]] under the microscope. | ||
* [[Autophagy]] is the mechanism through which [[osteocytes]] evade [[Oxidative stress|oxidative stress]]. | |||
* The capability of [[autophagy]] in cells decreases as they age, a major factor of aging. | |||
* As [[osteocytes]] grow, viability of cells decrease thereby decreasing the bone mass density.<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> | |||
* [[Autophagy]] is the mechanism | |||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
| |||
| |||
[[Category:Medicine]] | |||
[[Category:Endocrinology]] | |||
[[Category:Up-To-Date]] | |||
Latest revision as of 23:28, 29 July 2020
|
Osteoporosis Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Medical Therapy |
|
Case Studies |
|
Osteoporosis pathophysiology On the Web |
|
American Roentgen Ray Society Images of Osteoporosis pathophysiology |
|
Risk calculators and risk factors for Osteoporosis pathophysiology |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Eiman Ghaffarpasand, M.D. [2]
Overview
The pathophysiology of osteoporosis consists of an imbalance between bone resorption and bone formation. Major factors contributing to the development of osteoporosis include estrogen deficit and aging. The main mechanism, by which these factors might lead to osteoporosis is reactive oxygen species (ROS) induced damage to osteocytes. Decreased capability of osteocyte autophagy is another important issue; which makes them vulnerable to oxidative stresses. Genes involved in the pathogenesis of osteoporosis can be categorized into four main groups namely, osteoblast regulatory genes, osteoclast regulatory genes, bone matrix elements genes, and hormone/receptor genes.
Pathophysiology
Osteoporosis is mainly defined as bone mass loss and micro-architectural deterioration in bones. The final outcome of osteoporosis is fracture.
Pathogenesis
- In normal bone, there is constant remodeling of bone matrix. The process takes place in bone multicellular units (BMUs).[1][2]
- The process through which loss of bone mass occurs is the activation of osteoclastogenic pathway.
Osteoclastogenic pathway
- The two main cells involved in osteoclastogenic pathway are osteoblasts and osteoclasts.
- Bone resorption is caused by osteoclasts, after which new bone is deposited by osteoblasts.
- Osteoclasts determine the final outcome of bone resorption.[2][3]
- Normal balance between osteoblast and osteoclast activities within a bone is influenced by macrophages and innate adaptive immunity. This leads to the formation of a normal bone.
- Whenever there is a disturbance of this balance leading to increased osteoclastic activity relative to osteoblastic activity, the result is resorption, and eventual bone mass loss.[2]
Role of Hormones
- In addition to estrogen, calcium 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) increasing bone resorption in a bid to ensure adequate calcium levels 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]
Manolagas Theory
- Manolagas in 2010, suggested that main pathogenesis of osteoporosis shifted from estrogen-based theory to age-related issue.
- The theory consists of reactive oxygen species (ROS) as the main factor involved in the osteoporosis.
- According to Manolagas theory, loss of estrogen and androgen in the body would make bone tissue more vulnerable to ROS, making 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 needed for formation of osteoclasts.
Xiong Theory
- Xiong proposed that osteoblast and its progenitor cells are not the main sources of RANKL essential for osteoclast formation and remodeling in adult bones.
- Osteoprotegerin (OPG) binds RANKL before it has an opportunity to bind to RANK thereby suppressing 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 signaling pathway is recognized, but not clearly understood.
Genetics
Genes involved in the pathogenesis of osteoporosis can be categorized into four main groups. Mutation in any of these genes can lead to the development of some rare diseases. These genes include:
- Osteoblast regulatory genes
- Osteoclast regulatory genes
- Bone matrix elements genes
- Hormone/receptor genes.
| Group | Gene | Function | Related Disease |
|---|---|---|---|
| Osteoblast regulatory | Lipoprotein receptor-related protein 5 (LRP5) | Co-receptors for canonical Wnt signalling pathway | Osteoporosis-pseudoglioma syndrome (OPPG) High bone mass (HBM) disease |
| Transforming growth factor (TGF)-β1 | Effects on both osteoblast and osteoclast function, in vitro | Camurati-Engelmann (CED) disease | |
| Bone morphogenic proteins (BMPs) | Modulation of bone mineral density (BMD) along with limited roles in limb differentiation | Low bone mineral density (BMD) Osteoporosis | |
| Sclerostin | Inhibitory effects on Wnt signaling pathway | Van Buchem bone dysplasia Sclerosteosis bone dysplasia | |
| Core binding factor A1 (CBFA1) | Differentiate osteoblasts in order to bone formation | Cleidocranial dysplasia (CCD) | |
| Osteoclast regulatory | Cathepsin K | Regulating bone mineral density (BMD) with influencing osteoblasts and osteoclasts | Pycnodysostosis syndrome |
| Vacuolar proton pump a3 subunit (TCIRG1) | Osteoclast-specific proton pump generation | Osteopetrosis, recessive forms | |
| Chloride Channel 7 (CLCN7) | Coding chloride channels frequently expressed in osteoclasts | Osteopetrosis, severe forms | |
| Bone matrix element | Collagen type Iα I | Major conforming element in the bones | Osteogenesis imperfecta |
| Hormone and receptor | Vitamin D receptor (VDR) | Modulating vitamin D effects on bone formation | Vitamin D-resistant rickets |
| Estrogen receptor α | Influences fracture risk independent of an effect on bone mineral density (BMD) | Bone mass loss Osteoporosis |
- Wnt pathway is a critical pathway in developing various organs, such as extremities, central nervous system (CNS), 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.
- OPPG is osteoporosis along with blindness due to vitreous opacity while HBM is an abnormal increase of bone mineral density (BMD).[7][8][9]
Transforming growth factor (TGF)-β1
- The major family of TGF-β plays an important role in cell differentiation before and after birth.
- The most important member of the family in bone and fibrous tissues is TGF-β1, encoded by TGF-β1 gene.
- TGF-β1 plays the main role in determining osteoporosis susceptibility.
- If TGF-β gene becomes inactivated, it may result in major inflammation and severe osteoporosis.
- Polymorphisms within the intron 4 of the TGF-β1 gene has been shown to be the main cause of severe osteoporosis.
- Mutations in TGF-β1 gene causes Camurati-Engelmann (CED) disease, which is a rare disease of hyperostosis and sclerosis of long bones metaphysis.[10][11]
Bone morphogenic proteins (BMPs)
- Various changes in different codon location among the gene sequence have been proved to cause low bone mineral density (BMD) and also osteoporosis in patients.[12]
Sclerostin
- Sclerostin is a protein with cysteine contained knots in its structure that share some homologous sequences with anti-BMP proteins.
- SOST gene has a major role in BMD regulations, while the patient with heterozygous mutation may be asymptomatic they usually have higher BMD.
- 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.
- The mutations in the SOST gene may lead to van Buchem and Sclerosteosis bone dysplasias. These diseases are mainly severe osteosclerosis of skull, mandible, or any other trabecular bones.
- Sclerosteosis is more severe than van Buchem disease and mainly involves the upper extremity bones.[13][14][15]
Core binding factor A1 (CBFA1)
- CBFA1 is a major gene in bone formation. Laboratory animals with a mutated version or without the wild version of CBFA1 gene have failure of development of bone.
- The major role of the gene is to differentiate osteoblasts in order to construct the bones.
- Lack of the CBFA1 gene in the human body may lead to cleidocranial dysplasia (CCD), a disease in which patient has clavicular hypoplasia or complete aplasia, patent fontanels, short stature, teeth abnormalities, and other skeletal deformities.[16]
Cathepsin K
- A mutation in cathepsin K gene may cause Pycnodysostosis syndrome that is a rare syndrome of bone dysplasia along with osteosclerosis and short stature.[17]
Vacuolar proton pump a3 subunit (TCIRG1)
- It seems that this gene has some role in the regulation of bone mineral density (BMD).
- The majority of recessive forms of osteopetrosis are caused by inactivation of TCIRG1 gene.[18]
Chloride channel 7 (CLCN7)
- It controls the acidification of the environment and facilitate the resorption of the bone.
- Inactivation mutations of the gene may lead to severe forms of osteopetrosis.[15]
Collagen type Iα I
- Collagen type 1 gene is one of the most important genes in osteoporosis as collagen type 1 is the major conforming element in the bones.
- mutation in the collagen type 1 gene may cause osteogenesis imperfecta, in which the bone mineral density (BMD) is increased and the bones become fragile.[19]
Associated conditions
- Aging
- Anorexia nervosa
- Calcium abnormalities
- Chronic corticosteroid use
- Chronic renal failure
- Deep vein thrombosis (DVT)
- Fractures
- Gonadal dysgenesis
- Hyperparathyroidism
- Hypophosphatemic rickets
- Immobility
- Menopause
- Multiple myeloma
- Mixed connective tissue disease
- Paget's disease of bone
- Primary hypoparathyroidism
- Short stature
Gross pathology
|
On gross pathology, decreased bone density and small pores in diaphysis of bones are characteristic findings of osteoporosis. In advanced forms of the disease some pathological fractures may be seen. |
 |
Microscopic pathology
- Bone with osteoporosis shows increased number of osteoclasts and decreased number of osteoblasts under the microscope.
- Autophagy is the mechanism through which osteocytes evade oxidative stress.
- The capability of autophagy in cells decreases as they age, a major factor of aging.
- As osteocytes grow, viability of cells decrease thereby decreasing the bone mass density.[21]
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.
- ↑ Johnson ML, Harnish K, Nusse R, Van Hul W (2004). "LRP5 and Wnt signaling: a union made for bone". J. Bone Miner. Res. 19 (11): 1749–57. doi:10.1359/JBMR.040816. PMID 15476573.
- ↑ Gong Y, Vikkula M, Boon L, Liu J, Beighton P, Ramesar R; et al. (1996). "Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13". Am J Hum Genet. 59 (1): 146–51. PMC 1915094. PMID 8659519.
- ↑ Johnson ML, Gong G, Kimberling W, Reckér SM, Kimmel DB, Recker RB (1997). "Linkage of a gene causing high bone mass to human chromosome 11 (11q12-13)". Am. J. Hum. Genet. 60 (6): 1326–32. PMC 1716125. PMID 9199553.
- ↑ Geiser AG, Zeng QQ, Sato M, Helvering LM, Hirano T, Turner CH (1998). "Decreased bone mass and bone elasticity in mice lacking the transforming growth factor-beta1 gene". Bone. 23 (2): 87–93. PMID 9701466.
- ↑ Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, Yamada K, Kondo S, Ikegawa S, Nishimura G, Fukushima Y, Nakagomi T, Saito H, Sugimoto T, Kamegaya M, Hisa K, Murray JC, Taniguchi N, Niikawa N, Yoshiura K (2000). "Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease". Nat. Genet. 26 (1): 19–20. doi:10.1038/79128. PMID 10973241.
- ↑ Seemann P, Schwappacher R, Kjaer KW, Krakow D, Lehmann K, Dawson K, Stricker S, Pohl J, Plöger F, Staub E, Nickel J, Sebald W, Knaus P, Mundlos S (2005). "Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2". J. Clin. Invest. 115 (9): 2373–81. doi:10.1172/JCI25118. PMC 1190374. PMID 16127465.
- ↑ van Bezooijen, Rutger L.; Roelen, Bernard A.J.; Visser, Annemieke; van der Wee-Pals, Lianne; de Wilt, Edwin; Karperien, Marcel; Hamersma, Herman; Papapoulos, Socrates E.; ten Dijke, Peter; Löwik, Clemens W.G.M. (2004). "Sclerostin Is an Osteocyte-expressed Negative Regulator of Bone Formation, But Not a Classical BMP Antagonist". The Journal of Experimental Medicine. 199 (6): 805–814. doi:10.1084/jem.20031454. ISSN 0022-1007.
- ↑ Beighton P, Barnard A, Hamersma H, van der Wouden A (1984). "The syndromic status of sclerosteosis and van Buchem disease". Clin. Genet. 25 (2): 175–81. PMID 6323069.
- ↑ 15.0 15.1 Balemans W, Van Wesenbeeck L, Van Hul W (2005). "A clinical and molecular overview of the human osteopetroses". Calcif. Tissue Int. 77 (5): 263–74. doi:10.1007/s00223-005-0027-6. PMID 16307387.
- ↑ Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ (1997). "Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development". Cell. 89 (5): 765–71. PMID 9182764.
- ↑ Gelb, B. D.; Shi, G.-P.; Chapman, H. A.; Desnick, R. J. (1996). "Pycnodysostosis, a Lysosomal Disease Caused by Cathepsin K Deficiency". Science. 273 (5279): 1236–1238. doi:10.1126/science.273.5279.1236. ISSN 0036-8075.
- ↑ Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A (2000). "Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis". Nat. Genet. 25 (3): 343–6. doi:10.1038/77131. PMID 10888887.
- ↑ Boyde A, Travers R, Glorieux FH, Jones SJ (1999). "The mineralization density of iliac crest bone from children with osteogenesis imperfecta". Calcif. Tissue Int. 64 (3): 185–90. PMID 10024373.
- ↑ http://www.osseon.com/osteoporosis-overview/, CC0, https://commons.wikimedia.org/w/index.php?curid=43317280
- ↑ 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.