Vías de señalización anabólicas en el hueso y su potencial aplicación en la terapéutica

Para el manejo actual de la osteoporosis contamos con la terapia antirresortiva, que estabiliza la arquitectura ósea sin lograr su restauración y la anabólica (teriparatida: único aprobado por la FDA) que restaura y aumenta la masa ósea. La identificación de reguladores moleculares con efecto anabólico sobre el hueso ha permitido el desarrollo de nuevas terapias para el manejo de esta patología cada vez más prevalente.
La vía de señalización Wnt/?-catenina aumenta la masa ósea a través de la diferenciación de células mesenquimales hacia osteoblastos y mediante el estímulo de la replicación de preosteoblastos e inhibición de la apoptosis de osteoblastos y osteocitos, siendo las proteínas esclerostina y DKK1 (Dickko- pf 1) sus principales antagonistas. Se encuentran actualmente en desarrollo anticuerpos monoclonales humanizados contra estas proteínas (Ac anti esclerostina y anti DDK1) que tienen a un efecto formador de hueso.
Otra alternativa de uso local es la Proteína Morfogénica de Hueso 2, recombinante humana (rhBMP-2), con capacidad osteogénica, que ha demostrado aumentar la resistencia ósea en zonas de fracturas, acelerando la consolidación de las mismas.
Estos nuevos reguladores del remodelado óseo representan una alternativa terapéutica de la osteoporosis y otros trastornos asociados al desequilibrio entre la resorción y la formación ósea.

Summary
The current management of osteoporosis includes antiresorptive therapy, which stabilizes bone architecture without achieving its restoration, and anabolic therapy (Teriparatide: the only agent approved thus far by the FDA), which restores and increases bone mass. The identification of molecular regulators with anabolic effect on bone has allowed for developing new therapies for the management of this increasingly prevalent condition.
The Wnt/?-catenin signaling pathway increases bone mass via differentiation of mesenchymal cells into osteoblasts, stimulation of pre-osteoblasts replication and inhibition of the apoptosis of osteoblasts and osteocytes, with the proteins Sclerostin and DKK1 (Dickkopf 1) being its main antagonists. Humanized monoclonal antibodies against these proteins (anti-sclerostin and anti-DDK1 Ab), which have bone forming effects, are currently being developed.
Another alternative is the local use of human recombinant bone morphogenetic protein 2, (rhBMP-2), a protein with osteogenic capacity, which has been shown to increase bone strength at fracture areas, accelerating their consolidation.
These new bone remodeling regulators represent a therapeutic alternative for osteoporosis and other disorders associated with an imbalance between bone resorption and formation.

1. Konstantinos A. Toulis, Athanasios D. Anastasilakis, Stergios A. Polyzos, Polyzois Makras. Targeting the osteoblast: approved and experimental anabolic agents for the treatment of osteoporosis. HORMONES 2011;10(3):174-195.
2. Canalis E. Update in New Anabolic Therapies for Osteoporosis. J Clin Endocrinol Metab 2010; 95: 1496 –1504.
3. Baron R, Hesse E. Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives. J Clin Endocrinol Metab 2012;97: 311–325.
4. Lippuner k. The future of osteoporosis treatment a research update. Swiss Med Wkly 2012;142:w13624.
5. Canalis E, Giustina A, Bilezikian J. Mechanisms of Anabolic Therapies for Osteoporosis. N Engl J Med 2007;357:905-16.
6. Lewiecki E Michael. Monoclonal antibodies for the treatment of osteoporosis. Expert Opin. Biol. Ther 2013;13(2):183-196.
7. Krishnan V, Bryant H,1 MacDougald O. Regulation of bone mass by Wnt signaling. J. Clin. Invest 2006;116:1202–1209.
8. Pierre J. Marie. Transcription factors controlling osteoblastogenesis. Archives of Biochemistry and Biophysics 2008; 473:98–105.
9. Piters E, Boudin E, Van Hul W. Wnt signaling: A win for bone. Archives of Biochemistry and Biophysics 2008;473:112–116.
10. Daoussis D, Andonopoulos A. The Emerging Role of Dickkopf-1 in Bone Biology: Is It the Main Switch Controlling Bone and Joint Remodeling?. Semin Arthritis Rheum 2011;41:170-177.
11. Veverka V, Henry A, Slocombe P, Ventom A, Mulloy B, Muskett F, et al. Characterization of the Structural Features and Interactions of Sclerostin. J. Biol. Chem 2009;284:10890-10900.
12. Hua Zhu Ke, Richards W, Li X, Ominsky M. Sclerostin and Dickkopf-1 as Therapeutic Targets in Bone Diseases. Endocrine Reviews 2012;33(5):747–783.
13. Lewiecki E Michael. Sclerostin monoclonal antibody therapy with AMG 785: a potential treatment for osteoporosis. Expert Opin. Biol. Ther 2011; 11(1):117-127.
14. Costa A, Bilezikian J. Sclerostin: Therapeutic Horizons Based Upon Its Actions. Curr Osteoporos Rep 2012;10:64–72.
15. Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-Dose, Placebo-Controlled, Randomized Study of AMG 785, a Sclerostin Monoclonal Antibody. Journal of Bone and Mineral Research 2011; 26(1):19–26.
16. McClung M, Grauer A, Boonen S, Bolognese M, Brown J, Diez-Perez A, et al. Romosozumab in Postmenopausal Women with Low Bone Mineral Density. N Engl J Med 2014;370:412-20.
17. Clinicaltrials.gov. Number, NCT01101061. A Single-dose Study Evaluating AMG 785 in Healthy Postmenopausal Japanese Women.
18. Clinicaltrials.gov. Number, NCT00950950. A Study to Evaluate the Effect of AMG 785 on Bone Quality of the Forearm in Postmenopausal Women With Low Bone Mass.
19. Clinicaltrials.gov. Number, NCT01833754. Study of Romosozumab (AMG 785) Administered to Healthy Subjects and Subjects With Stage 4 Renal Impairment or Stage 5 Renal Impairment Requiring Hemodialysis.
20. Clinicaltrials.gov. Number, NCT01588509. Transition From Alendronate to AMG 785.
21. Clinicaltrials.gov. Number, NCT00896532. Phase 2 Study of AMG 785 in Postmenopausal Women With Low Bone Mineral Density.
22. Clinicaltrials.gov. Number, NCT01796301. An Open-label Study to Evaluate the Effect of Treatment With AMG 785 or Teriparatide in Postmenopausal Women (STRUCTURE).
23. Clinicaltrials.gov. Number, NCT01631214. Study to Determine the Efficacy and Safety of Romosozumab in the Treatment of Postmenopausal Women With Osteoporosis.
24. Clinicaltrials.gov. Number, NCT00902356. A First-in-human Study Evaluating AMG 167 in Healthy Men and Postmenopausal Women.
25. Clinicaltrials.gov. Number, NCT01101048. An Ascending Multiple Dose Study Evaluating AMG 167 in Healthy Men and Postmenopausal Women With Low Bone Mineral Density.
26. Clinicaltrials.gov. Number, NCT01742078. A Study of LY2541546 in Healthy Postmenopausal Women.
27. Clinicaltrials.gov. Number, NCT01742091. A Multiple Dose Study of LY2541546 in Healthy Postmenopausal Women.
28. Clinicaltrials.gov. Number, NCT01144377. A Study of LY2541546 in Women With Low Bone Mineral Density.
29. Clinicaltrials.gov. Number, NCT01406548. Safety and Efficacy of Multiple Dosing Regimens of BPS804 in Post Menopausal Women With Low Bone Mineral Density.
30. Rachner T, Khosla S, Hofbauer L. Osteoporosis: now and the future. Lancet 2011; 377: 1276–87.
31. Clinicaltrials.gov. Number, NCT01293487. Safety And To- lerability Study Of RN564 In Women With Osteopenia And Healthy Men.
32. Sosa-Garrocho M, Macías-Silva M. El factor de crecimiento transformante beta (TGF-?): funciones y vías de transducción. REB 2004;23 (1): 3-11.
33. Chen G, Deng C, Li Yi-Ping. TGF-? and BMP Signaling in Osteoblast Differentiation and Bone Formation. Int. J. Biol. Sci 2012; 8(2):272-288.
34. Clinicaltrials.gov. Number, NCT 00752557. Study Evaluating Changes In Bone Mineral Density (BMD), And Safety Of Rhbmp-2/CPM In Subjects With Decreased BMD.

osteoporosis
esclerostina
DKK1
anabólico óseo
Sclerostin
osteo-anabolic