Abstract
As the incidence of cystic fibrosis (CF) bone disease is increasing, we analyzed CF transmembrane conductance regulator (CFTR) deficient mice (CF mice) to gain pathogenic insights. In these studies comparing adult (14 wk) CF and C57BL/6J mice, both bone length and total area were decreased in CF mice. Metaphyseal trabecular and cortical density were also decreased, as well as diaphyseal cortical and total density. Trabecular bone volume was diminished in CF mice. Female CF mice revealed decreased trabecular width and number compared with C57BL/6J, whereas males demonstrated no difference in trabecular number. Female CF mice had reduced mineralizing surface and bone formation rates. Conversely, male CF mice had increased mineralizing surface, mineral apposition, and bone formation rates compared with C57BL/6J males. Bone formation rate was greater in males compared with female CF mice. Smaller bones with decreased density in CF, despite absent differences in osteoblast and osteoclast surfaces, suggest CF transmembrane conductance regulator influences bone cell activity rather than number. Differences in bone formation rate in CF mice are suggestive of inadequate bone formation in females but increased bone formation in males. This proanabolic observation in male CF mice is consistent with other clinical sex differences in CF.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- CF:
-
cystic fibrosis
- CFTR:
-
cystic fibrosis transmembrane conductance regulator
- BMD:
-
bone mineral density
References
Boat TF, Welsh MJ, Beaudet AL 1989 Cystic fibrosis. In: Scriver C, Beaudet A, Sly W, Valle D (eds) The Metabolic Basis of Inherited Disease. New York: McGraw-Hill, pp 2649–2680
2008 Cystic Fibrosis Foundation, Patient Registry 2006 Annual Report. Bethesda, Maryland
Cheung JC, Deber CM 2008 Misfolding of the cystic fibrosis transmembrane conductance regulator and disease. Biochemistry 47: 1465–1473
Orenstein DM, Winnie GB, Altman H 2002 Cystic fibrosis: a 2002 update. J Pediatr 140: 156–164
Aris RM, Renner JB, Winders AD, Buell HE, Riggs DB, Lester GE, Ontjes DA 1998 Increased rate of fractures and severe kyphosis: sequelae of living into adulthood with cystic fibrosis. Ann Intern Med 128: 186–193
Aris RM, Merkel PA, Bachrach LK, Borowitz DS, Boyle MP, Elkin SL, Guise TA, Hardin DS, Haworth CS, Holick MF, Joseph PM, O'Brien K, Tullis E, Watts NB, White TB 2005 Guide to bone health and disease in cystic fibrosis. J Clin Endocrinol Metab 90: 1888–1896
Boyle MP 2006 Update on maintaining bone health in cystic fibrosis. Curr Opin Pulm Med 12: 453–458
Rossini M, Del Marco A, Dal Santo F, Gatti D, Braggion C, James G, Adami S 2004 Prevalence and correlates of vertebral fractures in adults with cystic fibrosis. Bone 35: 771–776
Rovner AJ, Zemel BS, Leonard MB, Schall JI, Stallings VA 2005 Mild to moderate cystic fibrosis is not associated with increased fracture risk in children and adolescents. J Pediatr 147: 327–331
Latzin P, Griese M, Hermanns V, Kammer B 2005 Sternal fracture with fatal outcome in cystic fibrosis. Thorax 60: 616
Wolfenden LL, Judd SE, Shah R, Sanyal R, Ziegler TR, Tangpricha V 2008 Vitamin D and bone health in adults with cystic fibrosis. Clin Endocrinol (Oxf) 69: 374–381
Hecker TM, Aris RM 2004 Management of osteoporosis in adults with cystic fibrosis. Drugs 64: 133–147
Hardin DS, Rice J, Ahn C, Ferkol T, Howenstine M, Spears S, Prestidge C, Seilheimer DK, Shepherd R 2005 Growth hormone treatment enhances nutrition and growth in children with cystic fibrosis receiving enteral nutrition. J Pediatr 146: 324–328
Elkin SL, Vedi S, Bord S, Garrahan NJ, Hodson ME, Compston JE 2002 Histomorphometric analysis of bone biopsies from the iliac crest of adults with cystic fibrosis. Am J Respir Crit Care Med 166: 1470–1474
Goodman SB, Jiranek W, Petrow E, Yasko AW 2007 The effects of medications on bone. J Am Acad Orthop Surg 15: 450–460
Hofbauer LC, Gori F, Riggs BL, Lacey DL, Dunstan CR, Spelsberg TC, Khosla S 1999 Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis. Endocrinology 140: 4382–4389
Dif F, Marty C, Baudoin C, de Vernejoul MC, Levi G 2004 Severe osteopenia in CFTR-null mice. Bone 35: 595–603
Saeed Z, Guilbault C, De Sanctis JB, Henri J, Marion D, St-Arnaud R, Radzioch D 2008 Fenretinide prevents the development of osteoporosis in Cftr-KO mice. J Cyst Fibros 7: 222–230
Haston CK, Li W, Li A, Lafleur M, Henderson JE 2008 Persistent osteopenia in adult cystic fibrosis transmembrane conductance regulator-deficient mice. Am J Respir Crit Care Med 177: 309–315
Frost H 1983 Bone histomorphometry: choice of marking agent and labeling schedule. In: Recker R (ed) Bone Histomorphometry: Techniques and Interpretation. Boca Raton, FL: CRC Press, pp 37–52
Baron R, Vignery A, Neff L, Silvergate A, Santa Maria A 1983 Processing of undecalcified bone specimens for bone histomorphometry. In: Recker R (ed) Bone Histomorphometry: Techniques and Interpretation. Boca Raton, FL: CRC Press, pp 13–35
Aris RM, Ontjes DA, Buell HE, Blackwood AD, Lark RK, Caminiti M, Brown SA, Renner JB, Chalermskulrat W, Lester GE 2002 Abnormal bone turnover in cystic fibrosis adults. Osteoporos Int 13: 151–157
Shead EF, Haworth CS, Gunn E, Bilton D, Scott MA, Compston JE 2006 Osteoclastogenesis during infective exacerbations in patients with cystic fibrosis. Am J Respir Crit Care Med 174: 306–311
Johnston JA, Ward CL, Kopito RR 1998 Aggresomes: a cellular response to misfolded proteins. J Cell Biol 143: 1883–1898
Xu Y, Clark JC, Aronow BJ, Dey CR, Liu C, Wooldridge JL, Whitsett JA 2003 Transcriptional adaptation to cystic fibrosis transmembrane conductance regulator deficiency. J Biol Chem 278: 7674–7682
Virella-Lowell I, Herlihy JD, Liu B, Lopez C, Cruz P, Muller C, Baker HV, Flotte TR 2004 Effects of CFTR, interleukin-10, and Pseudomonas aeruginosa on gene expression profiles in a CF bronchial epithelial cell Line. Mol Ther 10: 562–573
Venkatakrishnan A, Stecenko AA, King G, Blackwell TR, Brigham KL, Christman JW, Blackwell TS 2000 Exaggerated activation of nuclear factor-kappaB and altered IkappaB-beta processing in cystic fibrosis bronchial epithelial cells. Am J Respir Cell Mol Biol 23: 396–403
Lory S, Ichikawa JK 2002 Pseudomonas-epithelial cell interactions dissected with DNA microarrays. Chest 121: 36S–39S
Kirchner KK, Wagener JS, Khan TZ, Copenhaver SC, Accurso FJ 1996 Increased DNA levels in bronchoalveolar lavage fluid obtained from infants with cystic fibrosis. Am J Respir Crit Care Med 154: 1426–1429
Heeckeren A, Walenga R, Konstan MW, Bonfield T, Davis PB, Ferkol T 1997 Excessive inflammatory response of cystic fibrosis mice to bronchopulmonary infection with Pseudomonas aeruginosa. J Clin Invest 100: 2810–2815
Haworth CS, Selby PL, Webb AK, Martin L, Elborn JS, Sharples LD, Adams JE 2004 Inflammatory related changes in bone mineral content in adults with cystic fibrosis. Thorax 59: 613–617
Haworth CS, Webb AK, Egan JJ, Selby PL, Hasleton PS, Bishop PW, Freemont TJ 2000 Bone histomorphometry in adult patients with cystic fibrosis. Chest 118: 434–439
Shead EF, Haworth CS, Condliffe AM, McKeon DJ, Scott MA, Compston JE 2007 Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human bone. Thorax 62: 650–651
Laursen EM, Lanng S, Rasmussen MH, Koch C, Skakkebaek NE, Muller J 1999 Normal spontaneous and stimulated GH levels despite decreased IGF-I concentrations in cystic fibrosis patients. Eur J Endocrinol 140: 315–321
Rosenberg LA, Schluchter MD, Parlow AF, Drumm ML 2006 Mouse as a model of growth retardation in cystic fibrosis. Pediatr Res 59: 191–195
Sawyer A, Bachrach LK, Fung E (eds) 2007 Bone Densitometry in Growing Patients. Totowa, NJ: Humana Press, pp 15–57
Jin R, Hodges CA, Drumm ML, Palmert MR 2006 The cystic fibrosis transmembrane conductance regulator (Cftr) modulates the timing of puberty in mice. J Med Genet 43: e29
Corey M, Edwards L, Levison H, Knowles M 1997 Longitudinal analysis of pulmonary function decline in patients with cystic fibrosis. J Pediatr 131: 809–814
Sweezey NB, Smith D, Corey M, Ellis L, Carpenter S, Tullis DE, Durie P, O'Brodovich HM 2007 Amiloride-insensitive nasal potential difference varies with the menstrual cycle in cystic fibrosis. Pediatr Pulmonol 42: 519–524
Levy H, Kalish LA, Cannon CL, Garcia KC, Gerard C, Goldmann D, Pier GB, Weiss ST, Colin AA 2008 Predictors of mucoid Pseudomonas colonization in cystic fibrosis patients. Pediatr Pulmonol 43: 463–471
Patterson JM, Wall M, Berge J, Milla C 2008 Gender differences in treatment adherence among youth with cystic fibrosis: development of a new questionnaire. J Cyst Fibros 7: 154–164
Milla CE, Billings J, Moran A 2005 Diabetes is associated with dramatically decreased survival in female but not male subjects with cystic fibrosis. Diabetes Care 28: 2141–2144
Hodges CA, Palmert MR, Drumm ML 2008 Infertility in females with cystic fibrosis is multifactorial: evidence from mouse models. Endocrinology 149: 2790–2797
Johannesson M, Gottlieb C, Hjelte L 1997 Delayed puberty in girls with cystic fibrosis despite good clinical status. Pediatrics 99: 29–34
Johannesson M, Landgren BM, Csemiczky G, Hjelte L, Gottlieb C 1998 Female patients with cystic fibrosis suffer from reproductive endocrinological disorders despite good clinical status. Hum Reprod 13: 2092–2097
Reiter EO, Stern RC, Root AW 1981 The reproductive endocrine system in cystic fibrosis. I. Basal gonadotropin and sex steroid levels. Am J Dis Child 135: 422–426
Reiter EO, Stern RC, Root AW 1982 The reproductive endocrine system in cystic fibrosis: 2. Changes in gonadotrophins and sex steroids following LHRH. Clin Endocrinol (Oxf) 16: 127–137
Stead RJ, Hodson ME, Batten JC, Adams J, Jacobs HS 1987 Amenorrhoea in cystic fibrosis. Clin Endocrinol (Oxf) 26: 187–195
Krum SA, Brown M 2008 Unraveling estrogen action in osteoporosis. Cell Cycle 7: 1348–1352
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pashuck, T., Franz, S., Altman, M. et al. Murine Model for Cystic Fibrosis Bone Disease Demonstrates Osteopenia and Sex-Related Differences in Bone Formation. Pediatr Res 65, 311–316 (2009). https://doi.org/10.1203/PDR.0b013e3181961e80
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/PDR.0b013e3181961e80
This article is cited by
-
Children and adolescents with cystic fibrosis display moderate bone microarchitecture abnormalities: data from high-resolution peripheral quantitative computed tomography
Osteoporosis International (2017)
-
Strategies and First Advances in the Development of Prevascularized Bone Implants
Current Molecular Biology Reports (2016)
-
Bone disease in cystic fibrosis: new pathogenic insights opening novel therapies
Osteoporosis International (2016)
-
CFTR induces extracellular acid sensing in Xenopus oocytes which activates endogenous Ca2+-activated Cl- conductance
Pflügers Archiv - European Journal of Physiology (2011)
