A bone growth factor is a growth factor that stimulates the growth of bone tissue.[1][2]

Known bone growth factors include insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), transforming growth factor beta (TGF-β), fibroblast growth factors (FGFs), platelet-derived growth factor (PDGF), parathyroid hormone-related peptide (PTHrP), bone morphogenetic proteins (BMPs), and certain members of the growth differentiation factor (GDF) group of proteins.[1][2][3]

The ultimate target of bone growth factors are osteoblasts, osteoclasts and fibroblasts. Human fibroblasts and osteoblasts were shown to be capable of producing bone growth factors after stimulation.[4]

Major hormones influencing bone growth and morphology include growth hormone (GH), androgens such as testosterone and dihydrotestosterone, and estrogens such as estradiol.[3][5]

Types

Transforming growth factor beta

Transforming growth factor beta (TGF-β) is a physiological regulator of osteoblast differentiation, and acts as a central component in the coupling of bone formation and its resorption during bone remodeling.[6]

Bone morphogenetic proteins

Bone morphogenetic proteins (BMPs) are proteins that are made of acidic polypeptides and belongs to the TGF-B family.[7] BMPs promote the regeneration of bone tissue and cartilage.[7] BMP exhibits osteoinductive activity. Osteoinductive activity leads to bone formation, activates mesenchymal cells to transform into osteoblasts which ultimately yield bone formation. BMP targets and binds to mesenchymal cells and activates a transmembrane serine/threonine kinase receptor which will lead to the phosphorylation of molecules called SMADS. SMADS are transcription factors that will induce osteoblast growth.[8]

Platelet derived growth factor

The majority of the substrates of platelet-derived growth factor (PDGF) exhibit similar structures to Src Homology 2 domain. These substrates will bind to the PDGFR receptors which will dimerize and autophosphorylate. This phosphorylation attracted PLC-gamma (induces cell proliferation), Ras (which goes through signaling cascade and acts as a transcription factor), phosphatidylinositol 3-kinase (PI3K) which also promotes a signaling cascade inducing transcription factors, and stress fiber formation, and induces the STAT pathway which activates transcription factors.[9]

Fibroblast growth factor

Platelet-derived growth factors (PDGFs) are polypeptides found in various tissues, including bone, where it was originally postulated that it could act as an autologous regulator of bone remodeling. This protein has been initially isolated in human platelets, and is composed of two different polypeptide chains A and B. The combination of these polypeptides form the homodimeric (AA) or (BB), or heterodimeric (AB) chains of PDGF.[10] Fibroblast growth factor (FGF) signaling cascade is started by the binding of 2 growth factors to the FGFR. Dimerization takes place and initiates the transphosphorylation of each receptor. These phosphorylation sites act as docking sites for proteins so they may induce downstream signaling. These proteins consist of FRS2-alpha and PLC-gamma. FRS2-alpha acts as a scaffold protein to hold GAB1 and GRB2 which then proteins bind to SHP2 and SOS. These several proteins act together to activates the Ras pathway (induces cell proliferation and differentiation) and the PI3K pathway (induces survival and cell fate determination). On the other side of the dimerized receptors, PLC-gamma activates DAG and IP3 which yield PKC and calcium ions. PKC and calcium will ultimately induce morphology, migration, and adhesion.[11]

Insulin-like growth factors

Insulin-like growth factors (IGF) assist bone growth in the body. IGF's are single-chain polypeptides that are similarly structured to insulin. There are 2 IGFs: Insulin-like growth factor 1 (IGF-1), and Insulin-like growth factor 2 (IGF-2). IGF-1 is induced by growth hormone (GH), and targets cartilage, stimulating cell bone cell proliferation. Studies carried out by Yakar S, Rosen CJ have shown in animal models that IGF-1 can enhance longitudinal growth, periosteal circumference, and bone mineral density.[12] IGF-1 is responsible for increasing overall body size, longitudinal bone size, and height, especially during puberty.[3][5]

Parathyroid hormone-related protein (PTHrP) is important for endochondral bone formation. Martin (2005) found that PTHrP stimulates bone formation by increasing osteoblast differentiation and reducing osteoblast apoptosis. This causes an increase in osteoblasts allowing for new bone cells to be formed. PTHrP also regulates osteoclast formation, further allowing for bone growth.[13]

Hormones

Estrogens cause the hips to widen and become rounded during puberty in females, and androgens cause the shoulders to broaden in males.[14][15][16] Estrogens mediate epiphyseal closure in both males and females.[3][5] Other hormones implicated in control of bone growth include thyroid hormone, parathyroid hormone,[17] calcitonin,[18] glucocorticoids such as cortisol, and vitamin D (calcitriol).[5] According to menoPAUSE, a blog from University of Rochester, estrogen causes females to have their fat distributed in their breasts, thighs, and along their pelvic area, implying that the fat can be used as an energy source for future pregnancies. For men, androgens (such as testosterone) increases male's muscle-to-fat ratio.Woods J. "What does Estrogen Have to Do with Belly Fat?".

Clinical significance

Potential treatment for osteoporosis

Osteoporosis is a bone disease where bone mass is less than the average and can increase fractures. Some causes that lead to osteoporosis is how old you are, and decreasing amount of estrogen, which is why it mainly occurs in older women (however it can also impact men as well).[19]

During a recent study performed at Children's Medical Center Research Institute at UT Southwestern, Bone Growth Factor Osteolectin (Clec11a) has also shown regenerative properties. Ovaries were removed from mice to simulate osteoporosis of post menopausal women. Results were based on daily injections of Osteolectin to determine the effects. This research showed an increase in bone volume of mice with bone loss after their ovaries were removed.[20]

To be more specific, in order to help people with osteoporosis, medication is used along with treating bone fractures. Clec11a is a glycoprotein that bone marrow expresses which Elifesciences states.[21]

Tendon treatment

Several studies have shown a correlation between the administration of bone growth factors and the amelioration of the tendon-to-bone healing. The focus of these studies was primarily on the anterior cruciate ligament (ACL) located in the knee, due to the high volume of incidences of injuries sustained by athletes.[22] The University of Dammam, King Fahd Hospital in Saudi Arabia was able to show that the addition of SHMSP bone growth factor via powder facilitated the process of tendon-graft healing in rabbits. Comparison of this SHMSP test group to the control group illustrated a higher level of formation and organization within the knee.  [22]

The Hospital for Special Surgery in New York conducted a similar study, in which a collagen sponge containing bone protein was implanted in the ACL of rabbits. In this case, the bone protein isolated from bovine femurs contained several bone morphogenetic proteins, which are part of an important signaling system that aides in the structure of bones.[23] As with the application of SHMSP, the inclusion of bone protein in the collagen sponge was seen to improve the healing process, when compared to control groups with the sponge alone or no sponge.[23]

In a separate study also implemented by the Hospital for Special Surgery as well as the University of California, treatment of the anterior cruciate ligament utilized the recombinant human bone morphogenic protein rhBMP-2 in two phases.[24] In phase one, the dosages of noggin, a regulator protein, as well as rhBMP-2 were properly calibrated, and in phase two these proteins carried on synthetic calcium phosphate matrix (CPM) were then injected into the ACL region. The results of this procedure also demonstrated an improvement in the collagen fiber formation between the tendon and the bone.[24] Hence, all three treatments were seen to improve the efficacy of tendon-to-bone healing via the different bone growth factors: SHMSP, bone protein, and rhBMP-2.

References

  1. 1 2 Mohan S, Baylink DJ (February 1991). "Bone growth factors". Clinical Orthopaedics and Related Research. 263 (263): 30–48. doi:10.1097/00003086-199102000-00004. PMID 1993386.
  2. 1 2 Baylink DJ, Finkelman RD, Mohan S (December 1993). "Growth factors to stimulate bone formation". Journal of Bone and Mineral Research. 8 (Suppl 2): S565-72. doi:10.1002/jbmr.5650081326. PMID 8122528. S2CID 42984375.
  3. 1 2 3 4 Shim KS (March 2015). "Pubertal growth and epiphyseal fusion". Annals of Pediatric Endocrinology & Metabolism. 20 (1): 8–12. doi:10.6065/apem.2015.20.1.8. PMC 4397276. PMID 25883921.
  4. ↑ Hausdorf J, Sievers B, Schmitt-Sody M, Jansson V, Maier M, Mayer-Wagner S (March 2011). "Stimulation of bone growth factor synthesis in human osteoblasts and fibroblasts after extracorporeal shock wave application". Archives of Orthopaedic and Trauma Surgery. 131 (3): 303–9. doi:10.1007/s00402-010-1166-4. PMID 20730589. S2CID 34915618.
  5. 1 2 3 4 Murray PG, Clayton PE (May 2013). "Endocrine control of growth". American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 163C (2): 76–85. doi:10.1002/ajmg.c.31357. PMID 23613426. S2CID 3129856.
  6. ↑ Erlebacher A, Filvaroff EH, Ye JQ, Derynck R (July 1998). "Osteoblastic responses to TGF-beta during bone remodeling". Molecular Biology of the Cell. 9 (7): 1903–18. doi:10.1091/mbc.9.7.1903. PMC 25433. PMID 9658179.
  7. 1 2 Ireland R (2020). Yeung CA (ed.). A Dictionary of Dentistry. doi:10.1093/acref/9780191828621.001.0001. ISBN 9780191828621.
  8. ↑ "Bone Growth Factors - Basic Science - Orthobullets". www.orthobullets.com. Retrieved 2021-05-05.
  9. ↑ Ying HZ, Chen Q, Zhang WY, Zhang HH, Ma Y, Zhang SZ, et al. (December 2017). "PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics (Review)". Molecular Medicine Reports. 16 (6): 7879–7889. doi:10.3892/mmr.2017.7641. PMC 5779870. PMID 28983598.
  10. ↑ Canalis E, McCarthy TL, Centrella M (September 1989). "Effects of platelet-derived growth factor on bone formation in vitro". Journal of Cellular Physiology. 140 (3): 530–7. doi:10.1002/jcp.1041400319. PMID 2777891. S2CID 43713808.
  11. ↑ Gimenez-Gallego G, Rodkey J, Bennett C, Rios-Candelore M, DiSalvo J, Thomas K (December 1985). "Brain-derived acidic fibroblast growth factor: complete amino acid sequence and homologies". Science. 230 (4732): 1385–8. Bibcode:1985Sci...230.1385G. doi:10.1126/science.4071057. PMID 4071057.
  12. ↑ Yakar S, Werner H, Rosen CJ (July 2018). "Insulin-like growth factors: actions on the skeleton". Journal of Molecular Endocrinology. 61 (1): T115–T137. doi:10.1530/JME-17-0298. PMC 5966339. PMID 29626053.
  13. ↑ Martin TJ (September 2005). "Osteoblast-derived PTHrP is a physiological regulator of bone formation". The Journal of Clinical Investigation. 115 (9): 2322–4. doi:10.1172/JCI26239. PMC 1193889. PMID 16138187.
  14. ↑ Epigenetics and Cancer. Academic Press. 23 November 2010. pp. 62–. ISBN 978-0-12-380865-3.
  15. ↑ Helmuth Nyborg (1 January 1994). Hormones, Sex, and Society: The Science of Physicology. Greenwood Publishing Group. pp. 51–. ISBN 978-0-275-94608-1.
  16. ↑ Shaffer D, Kipp K (1 January 2013). Developmental Psychology: Childhood and Adolescence. Cengage Learning. pp. 191–. ISBN 978-1-111-83452-4.
  17. ↑ Lombardi G, Di Somma C, Rubino M, Faggiano A, Vuolo L, Guerra E, et al. (July 2011). "The roles of parathyroid hormone in bone remodeling: prospects for novel therapeutics". Journal of Endocrinological Investigation. 34 (7 Suppl): 18–22. PMID 21985975.
  18. ↑ Carter PH, Schipani E (March 2006). "The roles of parathyroid hormone and calcitonin in bone remodeling: prospects for novel therapeutics". Endocrine, Metabolic & Immune Disorders Drug Targets. 6 (1): 59–76. doi:10.2174/187153006776056666. PMID 16611165.
  19. ↑ "Osteoporosis Overview". NIH Osteoporosis and Related Bone Diseases National Resource Center.
  20. ↑ "Scientists discover new bone-forming growth factor that reverses osteoporosis in mice". ScienceDaily. Retrieved 2019-12-05.
  21. ↑ Yue R, Shen B, Morrison SJ (December 2016). "Clec11a/osteolectin is an osteogenic growth factor that promotes the maintenance of the adult skeleton". eLife. 5. doi:10.7554/eLife.18782. PMC 5158134. PMID 27976999.
  22. 1 2 Al-Bluwi MT, Azam MQ, Sadat-Ali M (2016). "The effect of bone growth factor in the tendon to bone healing in anterior cruciate ligament reconstruction: An experimental study in rabbits". International Journal of Applied & Basic Medical Research. 6 (1): 23–7. doi:10.4103/2229-516X.174004. PMC 4765269. PMID 26958518.
  23. 1 2 Anderson K, Seneviratne AM, Izawa K, Atkinson BL, Potter HG, Rodeo SA (2001–2011). "Augmentation of tendon healing in an intraarticular bone tunnel with use of a bone growth factor". The American Journal of Sports Medicine. 29 (6): 689–98. doi:10.1177/03635465010290060301. PMID 11734478. S2CID 9946916.
  24. 1 2 Ma CB, Kawamura S, Deng XH, Ying L, Schneidkraut J, Hays P, Rodeo SA (April 2007). "Bone morphogenetic proteins-signaling plays a role in tendon-to-bone healing: a study of rhBMP-2 and noggin". The American Journal of Sports Medicine. 35 (4): 597–604. doi:10.1177/0363546506296312. PMID 17218656. S2CID 22750694.
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