Molecular Skeletal Biology
Final Report Abstract
The integrity of the bone tissue is preserved by an ongoing bone remodeling. In this wellbalanced process, bone matrix is removed by osteoclasts followed by the deposition of bone matrix by osteoblasts. During aging, this system becomes dysfunctional and more bone is removed than laid down. This can cause osteoporosis and fragility fractures. The treatment of fragility fractures comprises the use of anti-resorptive drugs and medicines that favor osteoblast-mediated bone formation. The latter includes the administration of a recombinant fragment of human Parathyroid Hormone comprising the first 34 amino acids (PTH 1-34) and an antibody against the Wnt signaling inhibitor sclerostin (Scl-Ab). PTH mediates its anabolic effect in part by reducing the expression of sclerostin. In this project we identified the homeodomain protein TG-interacting factor 1 (Tgif1) as a novel regulator of bone remodeling and as an essential component of the PTH anabolic action. Deletion of TG-interacting factor 1 (Tgif1) impaired osteoblast differentiation and activity, leading to a reduced bone formation. Deletion of Tgif1 in osteoblasts also decreased bone resorption due to an increased secretion of Semaphorin 3E. Tgif1 was further identified as a PTH target gene and PTH treatment decreased sclerostin expression in Tgif1-deficient bones to a much lesser degree than in control cells, which abrogated its anabolic function. Micro-RNAs (miRNAs) are regulatory molecules that control protein abundance. We identified Tgif1 as a downstream target of miR-19a and miR-19b, which were also uncovered as novel mediators of the bone anabolic effects of both PTH treatment and the activation of the canonical Wnt pathway. Therapeutic inhibition of miR-19a/b enhanced the bone anabolic effect of PTH therapy and reduced the bone loss in a mouse model of osteoporosis. Finally, we showed that the expression of miR-19a and miR-19b is increased in patients with low bone mass. Thus, inhibition of miR-19a/b may constitute an innovative therapeutic approach to develop novel or enhance existing bone anabolic therapies for patients suffering from fragility fractures. A second part of the project focuses on breast cancer bone metastases, which often cause a debilitating non-curable condition with osteolytic lesions and muscle weakness. We determined the expression of sclerostin in metastatic breast cancer cells. Pharmacological inhibition of sclerostin using an anti-sclerostin antibody (Scl-Ab) reduced metastases and prevented the cancer-induced bone destruction by augmenting osteoblast-mediated bone formation and reducing osteoclast-dependent bone resorption. Furthermore, Scl-Ab treatment re-established the muscle function by reconstituting an aberrant NF-kB and p38 signaling in the muscle tissue and by restoring a cancer-mediated impairment of muscle regeneration. This also improved the health and expanded the life span of cancer-bearing mice. Altogether, in this project we unraveled novel molecular pathways regulating bone remodeling and cancerinduced bone destruction and identified innovative concepts for potential novel pharmacotherapies.
Publications
- MicroRNA-34c inversely couples the biological functions of the runt-related transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma. J Biol Chem., 2013
van der Deen M, Taipaleenmäki H, Zhang Y, Teplyuk NM, Gupta A, Cinghu S, Shogren K, Maran A, Yaszemski MJ, Ling L, Cool SM, Leong DT, Dierkes C, Zustin J, Salto-Tellez M, Ito Y, Bae SC, Zielenska M, Squire JA, Lian JB, Stein JL, Zambetti GP, Jones SN, Galindo M, Hesse E, Stein GS, van Wijnen AJ
(See online at https://doi.org/10.1074/jbc.M112.445890) - Targeting of Runx2 by miRNA-135 and miRNA-203 impairs breast cancer metastasis and progression of osteolytic bone disease. Cancer Res., 2015
Taipaleenmäki H, Browne G, Akech J, Zustin J, van Wijnen AJ, Stein JL, Hesse E., Stein, G.S., Lian, J.B.
(See online at https://doi.org/10.1158/0008-5472.CAN-14-1026) - Antagonizing miR-218-5p attenuates Wnt signaling and reduces metastatic bone disease of triple negative breast cancer cells. Oncotarget, 2016
Taipaleenmäki H, Farina NH, van Wijnen AJ, Stein JL, Hesse E, Stein GS, Lian JB
(See online at https://doi.org/10.18632/oncotarget.12593) - Cortical Bone Fragility – Insights from sFRP4 Deficiency in Pyle Disease. N Engl J Med., 2016
Kiper POS, Saito H, Gori F, Unger S, Hesse E, Yamana K, Kiviranta R, Solban N, Liu J, Brommage R, Boduroglu K, Bonafé L, Campos-Xavier B, Dikoglu E, Eastell R, Gossiel F, Harshman K, Nishimura G, Girisha KM, Stevenson B, Takita H, Rivolta C, Superti-Furga A, Baron R
(See online at https://doi.org/10.1056/NEJMoa1509342) - Intramedullary Mg2Ag nails augment callus formation during fracture healing in mice. Acta Biomater., 2016
Jähn K, Saito H, Taipaleenmäki H, Gasser A, Hort N, Feyerabend F, Schlüter H, Rueger JM, Lehmann W, Willumeit-Römer R, Hesse E
(See online at https://doi.org/10.1016/j.actbio.2016.03.041) - Muscle and Bone: Combating the Evil Side of the Connection. J Bone Miner Res. 2016
Hesse E
(See online at https://doi.org/10.1002/jbmr.2912) - MicroRNAs in Bone Metastasis, Curr Osteoporos Rep., 2019
Hesse E, Taipaleenmäki H
(See online at https://doi.org/10.1007/s11914-019-00510-4) - Sarcopenia – Endocrinological und Neurological Aspects. Exp Clin Endocrinol Diabetes., 2019
Stangl MK, Böcker W, Chubanov V, Ferrari U, Fischereder M, Gudermann T, Hesse E, Meinke P, Reincke M, Reisch N, Saller MM, Seissler J, Schmidmaier R, Schoser B, Then C, Thorand B, Drey M
(See online at https://doi.org/10.1055/a-0672-1007) - Sclerostin inhibition alleviates breast cancer-induced bone metastases and muscle weakness. JCI Insight, 2019
Hesse E, Schröder S, Brandt D, Pamperin J, Saito H, Taipaleenmäki H
(See online at https://doi.org/10.1172/jci.insight.125543) - TG-interacting factor 1 (Tgif1)-deficiency attenuates bone remodeling and blunts the anabolic response to parathyroid hormone. Nat Commun., 2019
Saito H, Gasser A, Bolamperti S, Maeda M, Matthies L, Jähn K, Long CL, Schlüter H, Kwiatkowski M, Saini V, Pajevic PD, Bellido T, van Wijnen AJ, Mohammad KS, Guise TA, Taipaleenmäki H, Hesse E
(See online at https://doi.org/10.1038/s41467-019-08778-x)
