, Volume 49, Issue 3, pp 783–790 | Cite as

Sclerostin and DKK-1: two important regulators of bone metabolism in HIV-infected youths

  • Stefano MoraEmail author
  • Maria Puzzovio
  • Vania Giacomet
  • Valentina Fabiano
  • Katia Maruca
  • Silvia Capelli
  • Pilar Nannini
  • Giovanni Lombardi
  • Gian Vincenzo Zuccotti
Original Article


Reduced bone mineral density (BMD) and altered bone metabolism are common findings in HIV-infected patients. Increased bone formation has been described both in HIV-infected adults and children. Wnt ligands promote bone formation by stimulating osteoblast differentiation and their survival. Sclerostin and dickkopf factor 1 (DKK-1), Wnt antagonists, are important negative regulators of bone formation. We studied 86 HIV-infected patients whose ages ranged from 5.7 to 27.9 years. Patients were all on antiretroviral therapy, but seven who were naïve to treatment. Bone alkaline phosphatase (BAP), sclerostin, and DKK-1 were measured in serum by enzyme immunoassay. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine and in the whole skeleton. Biochemical indexes were also measured in 143 healthy controls (age range 4.5–27.4 years). HIV-infected patients had lower than normal BMD (spine P < 0.005, and whole skeleton P < 0.03). BAP measurements were significantly higher in HIV-infected patients than controls (P ≤ 0.05). Sclerostin and DKK-1 concentrations were markedly lower than in controls (P ≤ 0.0006, and P ≤ 0.03, respectively). The serum concentration of both analytes of patients naïve to antiretroviral treatment was not different from that of treated patients. No correlations were found between sclerostin, DKK-1, and bone mineral measurements. Our data confirm the alteration of bone metabolism pathways in HIV-infected individuals. The lower concentration of Wnt antagonists is consistent with the increased bone formation markers.


Sclerostin DKK-1 HIV infection Bone mineral density 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    P.W. Mallon, HIV and bone mineral density. Curr. Opin. Infect. Dis. 23, 1–8 (2010)PubMedCrossRefGoogle Scholar
  2. 2.
    S. Mora, I. Zamproni, G. Zuccotti, A. Viganò, Pediatric HIV infection and bone health: an emerging challenge. Front. Biosci. (Elite Ed) 2, 1265–1274 (2010)CrossRefGoogle Scholar
  3. 3.
    S. Mora, N. Sala, D. Bricalli, G. Zuin, G. Chiumello, A. Viganò, Bone mineral loss through increased bone turnover in HIV-infected children treated with highly active antiretroviral therapy. AIDS 15, 1823–1829 (2001)PubMedCrossRefGoogle Scholar
  4. 4.
    B.M. Tan, R.P. Nelson, M. James-Yarish, P.J. Emmanuel, S.J. Schurman, Bone metabolism in children with human immunodeficiency virus infection receiving highly active anti-retroviral therapy including a protease inhibitor. J. Pediatr. 139, 447–451 (2001)PubMedCrossRefGoogle Scholar
  5. 5.
    S. Mora, I. Zamproni, S. Beccio, R. Bianchi, V. Giacomet, A. Viganò, Longitudinal changes of bone mineral density and metabolism in antiretroviral-treated human immunodeficiency virus-infected children. J. Clin. Endocrinol. Metab. 89, 24–28 (2004)PubMedCrossRefGoogle Scholar
  6. 6.
    S. Mora, I. Zamproni, L. Cafarelli, V. Giacomet, P. Erba, G. Zuccotti, A. Viganò, Alterations in circulating osteoimmune factors may be responsible for high bone resorption rate in HIV-infected children and adolescents. AIDS 21, 1129–1135 (2007)PubMedCrossRefGoogle Scholar
  7. 7.
    A. Viganò, G.V. Zuccotti, M. Puzzovio, V. Pivetti, I. Zamproni, C. Cerini, V. Fabiano, V. Giacomet, S. Mora, Tenofovir disoproxil fumarate and bone mineral density: a 60-month longitudinal study in a cohort of HIV-infected youths. Antivir. Ther. (Lond) 15, 1053–1058 (2010)CrossRefGoogle Scholar
  8. 8.
    P. Aukrust, C. Haug, T. Ueland, E. Lien, F. Muller, T. Espevik, J. Bollerslev, S.S. Frøland, Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J. Clin. Endocrinol. Metab. 84, 145–150 (1999)PubMedGoogle Scholar
  9. 9.
    K. Mondy, K. Yarasheski, W.G. Powderly, M. Whyte, S. Claxton, D. DeMarco, M. Hoffmann, P. Tebas, Longitudinal evolution of bone mineral density and bone markers in human immunodeficiency virus-infected individuals. Clin. Infect. Dis. 36, 482–490 (2003)PubMedCrossRefGoogle Scholar
  10. 10.
    G. Madeddu, A. Spanu, P. Solinas, G.M. Calia, C. Lovigu, F. Chessa, M. Mannazzu, A. Falchi, M.S. Mura, G. Madeddu, Bone mass loss and vitamin D metabolism impairment in HIV patients receiving highly active antiretroviral therapy. Q. J. Nucl. Med. Mol. Imaging 48, 39–48 (2004)PubMedGoogle Scholar
  11. 11.
    H.J. Stellbrink, C. Orkin, J.R. Arribas, J. Compston, J. Gerstoft, E. Van Wijngaerden, A. Lazzarin, G. Rizzardini, H.G. Sprenger, J. Lambert, G. Sture, D. Leather, S. Hughes, P. Zucchi, H. Pearce, Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT Study. Clin. Infect. Dis. 51, 963–972 (2010)PubMedCrossRefGoogle Scholar
  12. 12.
    V. Krishnan, Regulation of bone mass by Wnt signaling. J. Clin. Invest. 116, 1202–1209 (2006)PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    R. Baron, G. Rawadi, Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology 148, 2635–2643 (2007)PubMedCrossRefGoogle Scholar
  14. 14.
    J.S. Butler, E.C. Dunning, D.W. Murray, P.P. Doran, J.M. O’Byrne, HIV-1 protein induced modulation of primary human osteoblast differentiation and function via a Wnt/β-catenin-dependent mechanism. J. Orthop. Res. 31, 218–226 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    E. Cacciari, S. Milani, A. Balsamo, E. Spada, G. Bona, L. Cavallo, F. Cerutti, L. Gargantini, N. Greggio, G. Tonini, A. Cicognani, Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J. Endocrinol. Invest. 29, 581–593 (2006)PubMedCrossRefGoogle Scholar
  16. 16.
    J.M. Tanner, R.H. Whitehouse, Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch. Dis. Child. 51, 170–179 (1976)PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    E.M. Lewiecki, C.M. Gordon, S. Baim, N. Binkley, J.P. Bilezikian, D.L. Kendler, D.B. Hans, S. Silverman, N.J. Bishop, M.B. Leonard, M.-L. Bianchi, H.J. Kalkwarf, C.B. Langman, H. Plotkin, F. Rauch, B.S. Zemel, Special report on the 2007 adult and pediatric Position Development Conferences of the International Society for Clinical Densitometry. Osteoporos. Int. 19, 1369–1378 (2008)PubMedCrossRefGoogle Scholar
  18. 18.
    G.K. Siberry, H. Li, D. Jacobson, Pediatric AIDS Clinical Trials Group (PACTG) 219/219C Study, Short Communication: Fracture risk by HIV infection status in perinatally HIV-exposed children. AIDS Res. Hum. Retroviruses 28, 247–250 (2012)PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    R. Bedimo, N.M. Maalouf, S. Zhang, H. Drechsler, P. Tebas, Osteoporotic fracture risk associated with cumulative exposure to tenofovir and other antiretroviral agents. AIDS 26, 825–831 (2012)PubMedCrossRefGoogle Scholar
  20. 20.
    J. Li, I. Sarosi, R.C. Cattley, J. Pretorius, F. Asuncion, M. Grisanti, S. Morony, S. Adamu, Z. Geng, W. Qiu, P. Kostenuik, D.L. Lacey, W.S. Simonet, B. Bolon, X. Qian, V. Shalhoub, M.S. Ominsky, H.Z. Ke, X. Li, W.G. Richards, Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 39, 754–766 (2006)PubMedCrossRefGoogle Scholar
  21. 21.
    F. Morvan, K. Boulukos, P. Clément-Lacroix, S. Roman Roman, I. Suc-Royer, B. Vayssière, P. Ammann, P. Martin, S. Pinho, P. Pognonec, P. Mollat, C. Niehrs, R. Baron, G. Rawadil, Deletion of a single allele of the Dkk1 gene leads to an increase in bone formation and bone mass. J. Bone Miner. Res. 21, 934–945 (2006)PubMedCrossRefGoogle Scholar
  22. 22.
    B.T. MacDonald, D.M. Joiner, S.M. Oyserman, P. Sharma, S.A. Goldstein, X. He, P.V. Hauschka, Bone mass is inversely proportional to Dkk1 levels in mice. Bone 41, 331–339 (2007)PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    M.K. Sutherland, J.C. Geoghegan, C. Yu, E. Turcott, J.E. Skonier, D.G. Winkler, J.A. Latham, Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. Bone 35, 828–835 (2004)PubMedCrossRefGoogle Scholar
  24. 24.
    D.L. Ellies, B. Viviano, J. McCarthy, J.-P. Rey, N. Itasaki, S. Saunders, R. Krumlauf, Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171 V to modulate Wnt activity. J. Bone Miner. Res. 21, 1738–1749 (2006)PubMedCrossRefGoogle Scholar
  25. 25.
    K.E. Poole, R.L. van Bezooijen, N. Loveridge, H. Hamersma, S.E. Papapoulos, C.W. Löwik, J. Reeve, Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation. FASEB J. 19, 1842–1844 (2005)PubMedGoogle Scholar
  26. 26.
    K. Amrein, S. Amrein, C. Drexler, H.P. Dimai, H. Dobnig, K. Pfeifer, A. Tomaschitz, T.R. Pieber, A. Fahrleitner-Pammer, Sclerostin and its association with physical activity, age, gender, body composition, and bone mineral content in healthy adults. J. Clin. Endocrinol. Metab. 97, 148–154 (2012)PubMedCrossRefGoogle Scholar
  27. 27.
    D. Aeberli, G. Schett, P. Eser, M. Seitz, P.M. Villiger, Serum Dkk-1 levels of DISH patients are not different from healthy controls. Joint Bone Spine 78, 422–423 (2011)PubMedCrossRefGoogle Scholar
  28. 28.
    M.S. Ardawi, H.A. Al-Kadi, A.A. Rouzi, M.H. Qari, Determinants of serum sclerostin in healthy pre- and postmenopausal women. J. Bone Miner. Res. 26, 2812–2822 (2011)PubMedCrossRefGoogle Scholar
  29. 29.
    A. Panayiotopoulos, N. Bhat, A. Bhangoo, Bone and vitamin D metabolism in HIV. Rev. Endocr. Metab. Disord. 14, 119–125 (2013)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Stefano Mora
    • 1
    Email author
  • Maria Puzzovio
    • 1
  • Vania Giacomet
    • 2
  • Valentina Fabiano
    • 3
  • Katia Maruca
    • 1
  • Silvia Capelli
    • 1
  • Pilar Nannini
    • 2
  • Giovanni Lombardi
    • 4
  • Gian Vincenzo Zuccotti
    • 3
  1. 1.Laboratory of Pediatric Endocrinology, Division of Genetics and Cell BiologyIRCCS San Raffaele Scientific InstituteMilanItaly
  2. 2.Department of Pediatrics, L. Sacco HospitalUniversity of MilanMilanItaly
  3. 3.Department of Pediatrics, Ospedale dei Bambini V. BuzziUniversity of MilanMilanItaly
  4. 4.Laboratory of Experimental Biochemistry & Molecular BiologyIRCCS Istituto Ortopedico GaleazziMilanItaly

Personalised recommendations