Osteoporosis pathophysiology
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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 basically is an imbalance between bone resorption and bone formation. Major contributing factors in 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) 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: osteoblast regulatory genes, osteoclast regulatory genes, bone matrix elements genes, and hormone/receptor genes.
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 mainly defined as bone mass loss and micro-architectural deterioration in bones. The final outcome in osteoporosis is fracture, caused by the predefined mechanisms.[1][2]
- The main mechanism, through which bone mass would be lost, is the activation of osteoclastogenic pathway. There are two main cells involved in the pathogenesis: osteoblasts and osteoclasts. Bone is reabsorbed by osteoclasts, after which new bone is deposited by osteoblasts.The main predictor of the 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 increased osteoclastic activity compared to osteoblastic activity; resulting in destruction more than construction, and eventual bone mass loss.[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]
- 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. He mentioned that loss of estrogen and androgen in the 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 sources 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]
- 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 signaling pathway is recognized, but less well understood.
Genetics
Genes involved in the pathogenesis of osteoporosis can be categorized into four main groups: the osteoblast regulatory genes, osteoclast regulatory genes, bone matrix elements genes, and hormone/receptor genes. Each of the genes can be mutated and lead to some rare diseases.
| 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 |
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. The LRP genes mutations may lead to two human rare diseases, osteoporosis-pseudoglioma syndrome (OPPG) and high bone mass (HBM) disease. OPPG is osteoporosis along with blindness due to vitreous opacity, while HBM is an abnormal increase of bone mineral density (BMD). [8][9][10]
Transforming growth factor (TGF)-β1
The major family of TGF-β has an important role in cell differentiation and also other functions before and after birth. But the most important member of the family in bone and fibrous tissues is TGF-β1, encoded by TGF-β1 gene. It can play the main role in determining osteoporosis susceptibility. In case the TGF-β gene becomes inactivated, it may result in major inflammation and also severe osteoporosis. Some polymorphism within the intron 4 of the TGF-β1 gene has shown to be the main cause of severe osteoporosis. Also, various polymorphisms in intron 5 would be associated with very low bone mineral density (BMD). Mutation in TGF-β1 gene causes Camurati-Engelmann (CED) disease, which is a rare disease of hyperostosis and sclerosis of long bones metaphysis. [11][12]
Bone morphogenic proteins (BMPs)
BMPs are also members of the superfamily of TGF-β proteins. The main role of BMP is modulation of bone mineral density along with limited roles in limb differentiation. The 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.[13]
Sclerostin
Sclerostin is a protein with cysteine contained knots in its structure and 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 but would have higher BMD. In some studies, it has found that SOST may cause a reduction in bone mass; over expression of the gene is contributed to the 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. The mutations in the SOST gene may lead to van Buchem and Sclerosteosis bone dysplasias. Both of the 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. [14][15][16]
Core binding factor A1 (CBFA1)
Regarding that the laboratory animals with a mutated version or without the wild version of CBFA1 gene have not any bone in their body, it seems that CBFA1 would be a major gene in bone formation. 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.[17]
Cathepsin K
The major role of cathepsin K is to regulate bone mineral density (BMD) with influencing osteoblasts and osteoclasts. A mutation in cathepsin K gene may cause Pycnodysostosis syndrome that is a rare syndrome of bone dysplasia along with osteosclerosis and short stature.[18]
Vacuolar proton pump a3 subunit (TCIRG1)
This gene mainly controls osteoclast-specific proton pump generation. 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.[19]
Chloride channel 7 (CLCN7)
CLCN7 is the gene coding for some types of chloride channels, frequently expressed in osteoclasts, that control the acidification of the environment and facilitate the resorption of the bone. Therefore, inactivation mutations of the gene may lead to severe forms of osteopetrosis.[16]
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 and 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.[20]
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
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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. |
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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 use to run away from oxidative stresses. The capability of autophagy in cells decreases as they age; 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.[22]
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.
- ↑ 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.
- ↑ 16.0 16.1 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.