Summary
Condylar cartilages were cultured in the form of organ cultures on top of collagen sponges in medium containing 2% fetal calf serum and were treated with 3.5–350 nM insulin for 6 days. Doses of 175 nM of insulin caused a marked increase (+96%) in DNA synthesis and in proteoglycan production (+74%), features that manifested themselves structurally by a 60% increase in overall size of the cultured explants. Using a tissue culture system comprised of cartilage progenitor cells, insulin was found to enhance the differentiation of the progenitor cells so that by 6 days in culture and appreciable nodule of differentiated chondrocytes developed. The latter was surrounded by perichondrial cells whereas the extracellular matrix within the newly formed, insulin-induced, nodule reacted positively for cartilagespecific antigens (type II collagen and bone sialoprotein). It is suggested that insulin induces a direct stimulatory effect on progenitor cell proliferation, cartilage differentiation, and extracellular matrix deposition.
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Laron Z, Karp M, Pertzelan A, Kauli R (1972) Insulin, growth and growth hormone. Isr J Med Sci 3:440–452
Karp M, Laron Z, Doron M (1973) Insulin secretion in children with constitutional familial short stature. J Pediatr 83:241–246
Laron Z (1981) Insulin as a growth hormone. In: Coller R et al (eds) Pediatric endocrinology. Raven Press, New York, pp 149–165
Salter J, Best C (1953) Insulin as a growth hormone. Br Med J 2:353–356
Susa JB, Widness JA, Hintz R, Liu F, Sehgal P, Schwartz R (1984) Somatomedins and insulin in diabetic pregnancies: effects on fetal macrosomia in the human and rhesus monkey. J Clin Endocrinol Metab 58:1099–1105
Schliwiller E, Guler JP, Merryweather J, Scandella C, Marki W, Zapf J, Froesch ER (1986) Growth retardation of insulindeficient diabetic rats by recombinant human insulin-like growth factor I.Nature 323:169–171
Hock JM, Centrella M, Canalis E (1988) Insulin-like growth factor I has independent effects on bone matrix formation and cell replication. Endocrinology 122:254–263
Strauss DS (1984) Growth stimulation actions of insulin in vitro and in vivo. Endocr Rev 5:356–369
Lebovitz HE, Eisenbarth GS (1975) Hormonal regulation of cartilage growth and metabolism. Vitam Horm 33:575–648
Vetter U, Zapf J, Heit W, Helbing G, Heinze E, Froesch ER, Teller WM (1986) Human fetal and adult chondrocytes. Effects of insulin-like growth factors I and II, insulin and growth hormone on clonal growth. J Clin Invest 77:1903–1908
Stevens RL, Nissley SP, Kimura JH, Rechler MM, Kaplan AJ, Hascall VC (1981) Effects of insulin and multiciplication-stimulating activity on proteoglycan biosynthesis in chondrocytes from the swarm rat chodrosarcoma. J Biol Chem 256: 2045–2052
Bembenek ME, Willis DH, Liberti JP (1982) The effect of insulin on collagen production in isolated chondrocytes. Biochem Biophys Res Commun 106:338–345
Lewinson D, Silbermann M (1986) Parathyroid hormone stimulates proliferation of chondroprogenitor cells in vitro. Calcif Tissue Int 38:155–162
Maor G, Hochberg Z, von der Mark K, Heinegard D, Silbermann M (1989) Human growth hormone enhances chondrogenesis and osteogenesis in a tissue culture system of chondroprogenitor cells. Endocrinology 125:1239–1245
Silbermann M, Maor G (1985) Receptor-mediated glucocorticoid inhibition of cell proliferation in mouse growth cartilage in vitro. Acta Endocrinol 108:343–350
Silbermann M, von der Mark K, Mirsky N, van Menxel M, Lewinson D (1987) Effects of increased doses of 1,25 dihydroxyvitamin D3 on matrix and DNA synthesis in condylar cartilage of suckling mice. Calcif Tissue Int 41:95–104
Maor G, Laron Z, Silbermann M (1989) In vitro effect of insulin-like growth factor I (IGF-I) and insulin on neonatal cartilage progenitor cells. Calcif Tissue Int 44:S11
Silbermann M, Iwamoto M, Kato Y, Suzuki F (1988) TGFβ stimulates DNA synthesis in precartilage cells but depresses alkaline phosphatase activity in chondrocytes and the calcification of the cartilage extracellular matrix in vitro. Calcif Tissue Int 42:S98
Silbermann M, Reddi AH, Hand AR, Leapman R, von der Mark K, Franzen A (1987) Chondroid bone arises from mesenchymal stem cells in organ cultures of mandibular condyles. J Craniofac Genet Dev Biol 7:59–79
Weiss A, von der Mark K, Silbermann M (1986) A tissue culture system supporting cartilage cell differentiation, extracellular mineralization, and subsequent bone formation, using mouse condylar progenitor cells. Cell Diff 19:103–113
Maor G, von der Mark K, Reddi AH, Heinegard D, Franzen A, Silbermann M (1987) Acceleration of cartilage and bone differentiation on collagen substrate. Collagen Rel Res 7:351–360
Kato Y, Koike T, Iwamoto M, Kinoshita M, Sato K, Hivaki Y, Suzuki F (1988) Effects of limited exposure of rabbit chondrocytes cultures to parathyroid hormone and dibutyryl adenosine 3′, 5′-monophosphate on cartilage characteristic proteoglycan synthesis. Endocrinology 122:1991–1997
von der Mark H, von der Mark K, Gay S (1976) Immunofluorescence studies of differential collagen synthesis during development of the chick embryo. Dev Biol 48:237–249
Holmdahl R, Rubin K, Klareskog L, Larsson E, Wigzell H (1986) Characterization of the antibody response in mice with type II collagen-induced arthritis, using monoclonal anti-type II collagen antibodies. Arthritis Rheum 29:400–410
Franzen A, Heingard D (1985) Isolation and characterization of two sialoproteins present only in bone calcified matrix. Biochem J 232:715–724
Silbermann M, Frommer J (1972) The nature of endochondral ossification in the mandibular condyle of the mouse. Anat Rec 172:659–668
Silbermann M, Tenenbaum H, Livne E, Leapman R, von der Mark K, Reddi AH (1987) The in vitro behavior of fetal condylar cartilage in serum-free hormone-supplemented medium. Bone 8:117–126
Copray JCVM, Brouwer N, Prins APA, Jansen HWB (1988) Effects of polypeptide growth factors on mandibular condylar cartilage of the rat in vitro. J Biol Buccule 16:109–117
Maor G, Laron Z, Ashot R, Silbermann M (in press) The growth of the murine-derived neonatal mandibular condyle is dependent on the paracrine activity of insulin-like growth factor I (IGF-I). Endocrinology
Goldstein RH, Poliks CF, Pilch PF, Smith BD, Fine A (1989) Stimulation of collagen formation by insulin and insulin-like growth factor I cultures of human lung fibroblasts. Endocrinology 124:964–970
Okajima T, Nakamura K, Zhang H, Ling N, Tanabe T, Yasuda T, Rosenfeld RG (1992) Sensitive colorimetric bioassays for insulin-like growth factor (IGF) stimulation of cell proliferation and glucose consumption: use in studies of IGF analysis. Endocrinology 130:2201–2212
Kemp SF, Mutchinic M, Hintz RL (1984) Hormonal control of protein synthesis in chick chondrocytes: a comparison of effects of insulin, somatomedin C and triiodothyronine. Acta Endocrinol 107:179–184
Alarid ET, Schlechter NL, Russell SM, Nicoll CS (1992) Evidence suggesting that insulin-like growth factor I is necessary for the tropic effects of insulin on cartilage growth in vivo. Endocrinology 139:2305–2309
Froger-Gaillard B, Hossenlopp P, Adolphe M, Binoux M (1989) Production of insulin-like growth factors and their binding proteins by rabbit articular chondrocytes: relationship with cell multiplication. Endocrinology 124:2365–2372
Flier JS, Usher P, Moses AC (1986) Monoclonal antibody to the type 1 insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts. Proc Natl Acad Sci USA 83:664–668
Zapf J, Schmidt CH, Froesch ER (1984) Biological and immunological properties of insulin-like growth factor (IGF) I and II. Clin Endocrinol Metab 13:3–30
Ullrich A, Bell JR, Chen EY, Herrera R, Petruzelli LM, Dull TJ, Gray A, Cousseus L, Liao YC, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J (1986) Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313:756–761
Roth RA (1988) Structure of the receptor for insulin-like growth factor II: the puzzle amplified. Science 239:1269–1271
Morgan DO, Jarnagin K, Roth RA (1986) Purification characterization of the receptor for insulin-like growth factor I. Biochemistry 25:5560–5564
Rosen OM (1987) After insulin binds. Science 237:1452–1458
Winter SJ, Turvey A, Forsyth IA (1989) Stimulation of DNA synthesis in cultures of ovine mamary epithelial cells by insulin and insulin-like growth factors. J Endocrinol 123:319–326
Kono T, Robinson FW, Blevins TL, Ezaki O (1982) Evidence that translocation of the glucose transport activity is the major mechanism of insulin action on glucose transport in fat cells. J Biol Chem 257:10942–10947
Mortimore GE, Mondon CE (1970) Inhibition by insulin of valine turnover in liver. J Biol Chem 245:2375–2383
Draznin B, Trowbridge M (1982) Inhibition of intracellular proteolysis by insulin in isolated rat hepatocytes. J Biol Chem 257: 11988–11993
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Maor, G., Silbermann, M., von der Mark, K. et al. Insulin enhances the growth of cartilage in organ and tissue cultures of mouse neonatal mandibular condyle. Calcif Tissue Int 52, 291–299 (1993). https://doi.org/10.1007/BF00296654
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DOI: https://doi.org/10.1007/BF00296654