Vol 68, No 6 (2017)
Review paper
Published online: 2017-11-30
The content of this article is also available in the following languages:
Polski
Polski
PAPP-A2 a new key regulator of growth
Abstract
Short stature is the main problem that paediatric endocrinologists have to grapple with. Endocrine disorders account for only 5% of patients with short stature, but this is still one of the most common causes of reports to the endocrine clinic and hospitalisation in the endocrine department. A properly functioning growth hormone/insulin-like growth factor (GH/IGF) axis is one of the most important factors in proper growth. A lot of genetic defects in this axis lead to syndromes marked by impaired growth, like Laron syndrome, mutations in the STAT5B, insulin-like growth factor 1 (IGF1), and insulin-like growth factor 1 receptor (IGF1R) and mutations in the acid labile subunit (ALS). Two proteases important for the proper functioning of the GH/IGF axis: pregnancy-associated plasma protein-A (PAPP-A) and pregnancy-associated plasma protein-A2 (PAPP-A2), have been described. The first description of the new syndrome of growth failure associated with mutation in the PAPP-A2 gene was given by Andrew Dauber et al. This review evaluates the current data concerning PAPP-A2 function, and particularly the effect of PAPP-A2 mutation on growth.
Keywords: growthshort statureGHIGF1PAPP-A2
References
- Melmed S, Yamashita S, Yamasaki H, et al. IGF-I receptor signalling: lessons from the somatotroph. Recent Prog Horm Res. 1996; 51: 189–215; discussion 215.
- Baxter RC. Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab. 2000; 278(6): E967–E976.
- Forbes BE, McCarthy P, Norton RS. Insulin-like growth factor binding proteins: a structural perspective. Front Endocrinol (Lausanne). 2012; 3: 38.
- Beattie J, Allan GJ, Lochrie JD, et al. Insulin-like growth factor-binding protein-5 (IGFBP-5): a critical member of the IGF axis. Biochem J. 2006; 395(1): 1–19.
- Farr M, Strübe J, Geppert HG, et al. Pregnancy-associated plasma protein-E (PAPP-E). Biochim Biophys Acta. 2000; 1493(3): 356–362.
- Boldt HB, Overgaard MT, Laursen LS, et al. Mutational analysis of the proteolytic domain of pregnancy-associated plasma protein-A (PAPP-A): classification as a metzincin. Biochem J. 2001; 358(Pt 2): 359–367.
- Overgaard MT, Boldt HB, Laursen LS, et al. Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase. J Biol Chem. 2001; 276(24): 21849–21853.
- Page NM, Butlin DJ, Lomthaisong K, et al. The characterization of pregnancy associated plasma protein-E and the identification of an alternative splice variant. Placenta. 2001; 22(8-9): 681–687.
- Govoni KE, Baylink DJ, Mohan S. The multi-functional role of insulin-like growth factor binding proteins in bone. Pediatr Nephrol. 2005; 20(3): 261–268.
- Mohan S, Richman C, Guo R, et al. Insulin-like growth factor regulates peak bone mineral density in mice by both growth hormone-dependent and -independent mechanisms. Endocrinology. 2003; 144(3): 929–936.
- Zhang W, Shen X, Wan C, et al. Effects of insulin and insulin-like growth factor 1 on osteoblast proliferation and differentiation: differential signalling via Akt and ERK. Cell Biochem Funct. 2012; 30(4): 297–302.
- Mohan S, Baylink DJ. IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. J Endocrnol. 2002; 175(1): 297–302.
- Miyakoshi N, Richman C, Kasukawa Y, et al. Evidence that IGF-binding protein-5 functions as a growth factor. J Clin Invest. 2001; 107(1): 73–81.
- De Meyts P, Palsgaard J, Sajid W, et al. Structural biology of insulin and IGF-1 receptors. Novartis Found Symp. 2004; 262: 160–71; discussion 171.
- Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995; 16(1): 3–34.
- Lawrence JB, Oxvig C, Overgaard MT, et al. The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A. Proc Natl Acad Sci U S A. 1999; 96(6): 3149–3153.
- Fowlkes JL. Insulin like growth factor-binding protein proteolysis an emerging paradigm in insulin like growth factor physiology. Trends Endocrinol Metab. 1997; 8(8): 299–306.
- Gaidamauskas E, Gyrup C, Boldt HB, et al. IGF dependent modulation of IGF binding protein (IGFBP) proteolysis by pregnancy-associated plasma protein-A (PAPP-A): multiple PAPP-A-IGFBP interaction sites. Biochim Biophys Acta. 2013; 1830(3): 2701–2709.
- Qin X, Byun D, Lau KH, et al. Evidence that the interaction between insulin-like growth factor (IGF)-II and IGF binding protein (IGFBP)-4 is essential for the action of the IGF-II-dependent IGFBP-4 protease. Arch Biochem Biophys. 2000; 379(2): 209–216.
- Bayes-Genis A, Schwartz RS, Lewis DA, et al. Insulin-like growth factor binding protein-4 protease produced by smooth muscle cells increases in the coronary artery after angioplasty. Arterioscler Thromb Vasc Biol. 2001; 21(3): 335–341.
- Overgaard MT, Haaning J, Boldt HB, et al. Expression of recombinant human pregnancy-associated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor. J Biol Chem. 2000; 275(40): 31128–31133.
- Conover CA, Oxvig C, Overgaard MT, et al. Evidence that the insulin-like growth factor binding protein-4 protease in human ovarian follicular fluid is pregnancy associated plasma protein-A. J Clin Endocrinol Metab. 1999; 84(12): 4742–4745.
- Overgaard MT, Boldt HB, Laursen LS, et al. Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase. J Biol Chem. 2001; 276(24): 21849–21853.
- Claussen M, Zapf J, Braulke T. Proteolysis of insulin-like growth factor binding protein-5 by pregnancy serum and amniotic fluid. Endocrinology. 1994; 134(4): 1964–1966.
- Yan X, Baxter RC, Firth SM. Involvement of pregnancy-associated plasma protein-A2 in insulin-like growth factor (IGF) binding protein-5 proteolysis during pregnancy: a potential mechanism for increasing IGF bioavailability. J Clin Endocrinol Metab. 2010; 95(3): 1412–1420.
- Lee KO, Oh Y, Giudice LC, et al. Identification of insulin-like growth factor-binding protein-3 (IGFBP-3) fragments and IGFBP-5 proteolytic activity in human seminal plasma: a comparison of normal and vasectomized patients. J Clin Endocrinol Metab. 1994; 79(5): 1367–1372.
- Imai Y, Busby WH, Smith CE, et al. Protease-resistant form of insulin-like growth factor-binding protein 5 is an inhibitor of insulin-like growth factor-I actions on porcine smooth muscle cells in culture. J Clin Invest. 1997; 100(10): 2596–2605.
- Resnick CE, Fielder PJ, Rosenfeld RG, et al. Characterization and hormonal regulation of a rat ovarian insulin-like growth factor binding protein-5 endopeptidase: an FSH-inducible granulosa cell-derived metalloprotease. Endocrinology. 1998; 139(3): 1249–1257.
- Conover CA, Kiefer MC. Regulation and biological effect of endogenous insulin-like growth factor binding protein-5 in human osteoblastic cells. J Clin Endocrinol Metab. 1993; 76(5): 1153–1159.
- Thrailkill KM, Quarles LD, Nagase H, et al. Characterization of insulin-like growth factor-binding protein 5-degrading proteases produced throughout murine osteoblast differentiation. Endocrinology. 1995; 136(8): 3527–3533.
- Busby WH, Nam TJ, Moralez A, et al. The complement component C1s is the protease that accounts for cleavage of insulin-like growth factor-binding protein-5 in fibroblast medium. J Biol Chem. 2000; 275(48): 37638–37644.
- Kjaer-Sorensen K, Engholm DH, Jepsen MR, et al. Papp-a2 modulates development of cranial cartilage and angiogenesis in zebrafish embryos. J Cell Sci. 2014; 127(Pt 23): 5027–5037.
- Christians JK, de Zwaan DR, Fung SH. Pregnancy associated plasma protein A2 (PAPP-A2) affects bone size and shape and contributes to natural variation in postnatal growth in mice. PLoS One. 2013; 8(2): e56260.
- Conover CA, Boldt HB, Bale LK, et al. Pregnancy-associated plasma protein-A2 (PAPP-A2): tissue expression and biological consequences of gene knockout in mice. Endocrinology. 2011; 152(7): 2837–2844.
- Amiri N, Christians JK. PAPP-A2 expression by osteoblasts is required for normal postnatal growth in mice. Growth Horm IGF Res. 2015; 25(6): 274–280.
- Yakar S, Courtland HW, Clemmons D. IGF-1 and bone: New discoveries from mouse models. J Bone Miner Res. 2010; 25(12): 2543–2552.
- Sheng MHC, Zhou XD, Bonewald LF, et al. Disruption of the insulin-like growth factor-1 gene in osteocytes impairs developmental bone growth in mice. Bone. 2013; 52(1): 133–144.
- Govoni KE, Lee SK, Chung YS, et al. Disruption of insulin-like growth factor-I expression in type IIalphaI collagen-expressing cells reduces bone length and width in mice. Physiol Genomics. 2007; 30(3): 354–362.
- Govoni KE, Wergedal JE, Florin L, et al. Conditional deletion of insulin-like growth factor-I in collagen type 1alpha2-expressing cells results in postnatal lethality and a dramatic reduction in bone accretion. Endocrinology. 2007; 148(12): 5706–5715.
- Kim HS. Role of insulin-like growth factor binding protein-3 in glucose and lipid metabolism. Ann Pediatr Endocrinol Metab. 2013; 18(1): 9–12.
- Ruan W, Lai M. Insulin-like growth factor binding protein: a possible marker for the metabolic syndrome? Acta Diabetol. 2010; 47(1): 5–14.
- Wheatcroft SB, Kearney MT. IGF-dependent and IGF-independent actions of IGF-binding protein-1 and -2: implications for metabolic homeostasis. Trends Endocrinol Metab. 2009; 20(4): 153–162.
- Christians JK, Bath AK, Amiri N. Pappa2 deletion alters IGFBPs but has little effect on glucose disposal or adiposity. Growth Horm IGF Res. 2015; 25(5): 232–239.
- Dauber A, Muñoz-Calvo MT, Barrios V, et al. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med. 2016; 8(4): 363–374.
- Muñoz-Calvo MT, Barrios V, Pozo J, et al. Treatment With Recombinant Human Insulin-Like Growth Factor-1 Improves Growth in Patients With PAPP-A2 Deficiency. J Clin Endocrinol Metab. 2016; 101(11): 3879–3883.
- David A, Hwa V, Metherell LA, et al. Evidence for a continuum of genetic, phenotypic, and biochemical abnormalities in children with growth hormone insensitivity. Endocr Rev. 2011; 32(4): 472–497.
- Amselem S, Duquesnoy P, Attree O, et al. Laron Dwarfism and Mutations of the Growth Hormone–Receptor Gene. N Engl J Med. 1989; 321(15): 989–995.
- Kofoed EM, Hwa V, Little B, et al. Growth hormone insensitivity associated with a STAT5b mutation. N Engl J Med. 2003; 349(12): 1139–1147.
- Woods KA, Camacho-Hübner C, Savage MO, et al. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 1996; 335(18): 1363–1367.
- Abuzzahab MJ, Schneider A, Goddard A, et al. Intrauterine Growth Retardation (IUGR) Study Group. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003; 349(23): 2211–2222.
- Rohde A, Obara-Moszyńska M. Idiopathic short stature, current knowlenge and perspectives- Review article. Pediatr Pol. ; 2017.
- Domené HM, Bengolea SV, Martínez AS, et al. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med. 2004; 350(6): 570–577.
![](https://journals.viamedica.pl/plugins/generic/popups/images/icons/close.png)