Robling Lab

Mechanical loading of the skeleton from daily activities determines to a large extent how the skeleton develops. Without proper exercise and loading activities, the skeleton will develop with insufficient strength, and osteoporotic fractures will eventually occur. Led by Alexander Robling, PhD this laboratory seeks to discover the molecular mechanisms by which bone tissue senses mechanical loading, by studying how several signal transduction pathways affect bone accumulation, and how cellular activity is altered by mechanical stimulation. This goal is addressed by investigating bone cell proliferation, differentiation and apoptosis, after mechanical loading in mice harboring various mutations in the Wnt/Akt/Bmp signaling pathways. The role of these pathways in mechanical disuse is also studied, using several in vivo models of disuse osteoporosis.

Get Research Updates

To stay current on the medical research work at IU School of Medicine’s statewide campuses, follow the IU School of Medicine research blog, where investigators throughout the school’s academic departments post updates about their work.

Active Research

Foundational in vivo experiments on osteocyte biology in space

Bone loss due to the weightlessness of space is a major health concern for astronauts that spend significant amounts of time in space. The development of effective countermeasures to bone loss in space requires a detailed understanding of the biological alterations among cells that control skeletal homeostasis. Those alterations can take on many forms, including chemical modifications to the genome (epigenetics), changes in the expression of certain genes (RNA transcription) and certain small nucleic acid chains that regulate protein production (microRNA), and changes in the physical properties of bone matrix, among others.

This project explores changes in osteocyte biology and bone matrix properties that are associated with long-term space flight, with the goal of elucidating new mechanisms to target for maintaining bone health during space travel. To this end, scientists in this lab proposes to study mice that have spent five weeks or four months aboard the International Space Station. The lab will look for changes in DNA, RNA, protein, using an “omics” approach to broadly capture biological changes induced by spaceflight. NASA (14-SB_Step2-0030)

Role of Src kinase in mechanically-induced bone formation

Pharmacologic manipulation of mechanotransduction signaling processes in bone cells has therapeutic potential. Mechanotransduction signaling mechanisms that suppress the stimulatory effects of loading (rather than focusing on signaling pathways that stimulate new bone formation) are targetable. The fundamental goal of this project is to manipulate mechanotransduction pathways so that modest levels of exercise can have ampilified anabolic effects.

Osteocytes (OCY), the most abundant cell type in bone, coordinate the response of bone to mechanical load. This lab team proposes that the tyrosine kinase Src functions in OCY as a novel suppressor of load-induced bone formation. Upon activation by mechanical stimuli, Src dissociates from integrins (membrane mechanosensors) and translocates to the nucleus as part of a multi-protein complex with Proline-rich Kinase-2 (Pyk2) and the methylated DNA binding protein Methyl-CpG Binding Domain Protein-2 (MBD2), to regulate epigenetics of key bone genes. Thus, OCYs may utilize a SrcPyk2-MBD2 “mechanosome” to promote or suppress anabolic or anti-catabolic bone genes by altering promoter associated CpG islands. This project dissects the molecular mechanisms through which Src inhibits bone formation using in vivo and in vitro approaches with the long term goal of better understanding the clinical and translational potential of Src inhibitors to enhance bone density and fracture susceptibility. National Institutes of Health (R01 AR69029)

Recent Publications

Robling AG, Drake MT, Papapoulos SE. (2017) Sclerostin: From bedside to bench, and back to bedside. Bone. 2017 Mar;96:1-2

Kedlaya R, Kang KS, Hong JM, Lim KE, Horan DJ, Divieti-Pajevic P, Robling AG (2016) Adult onset deletion of β-catenin in 10kbDmp1-expressing cells prevents intermittent PTH-induced bone gain. Endocrinol., 157(8):3047-57

Kang KS, Hong JM, Robling AG (2016) Postnatal β-catenin deletion from osteocytes/osteoblasts reduces structural adaptation to loading, but not load-induced bone formation. Bone, 88:138-45.

Robling AG, Kang KS, Bullock WA, Foster WH, Murugesh D, Loots GG, Genetos DC. (2016) Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation. Bone. 2016 Nov;92:180-188. doi: 10.1016/j.bone.2016.09.001.

Baumann AP, Aref MW, Turnbull TL, Robling AG, Niebur GL, Allen MR, Roeder RK (2015) Development of an in vivo rabbit ulnar loading model. Bone 75:55-61.

Niziolek, PJ, MacDonald BT, Kedlaya R, Zhang M, Bellido T, He X, Warman ML, Robling AG (2015) High-bone-mass causing mutant LRP5 receptors are resistant to endogenous inhibitors in vivo. J Bone Miner Res 30:1822-30.

Niziolek, PJ, Bullock WA, Warman ML, Robling AG (2015) Missense mutations in LRP5 associated with high bone mass protect the mouse skeleton from disuse- and ovariectomy-induced osteopenia. PLoS One 10: e140775.

Childress P, Stayrook KR, Alvarez MB, Wang Z, Shao Y, Hernandez-Buquer S, Mack JK, Grese ZR, He Y, Horan D, Pavalko FM, Warden SJ, Robling AG, Yang FC, Allen MR, Krishnan V, Liu Y, Bidwell JP. (2015) Genome-wide mapping and interrogation of the Nmp4 antianabolic bone axis. Mol Endocrinol. 29:1269-85.

Alam I, Alkhouli M, O’Riley RG, Wright WB, Acton D, Gray AK, Patel B, Reilly AM, Lim KE, Robling AG, Econs MJ (2015) Osteoblast-specific overexpression of human WNT16 increases both cortical and trabecular bone mass and structure in mice. Endocrinol. 157:722-36.

Ross RD, Mashiatulla M, Robling AG, Miller LM, Sumner DR (2015) Bone matrix composition following PTH treatment is not dependent on sclerostin status. Calcif Tissue Int. 98:149-57.

Research Team

Led by Alexander Robling, PhD, research team members include Kyung-Eun Lim, PhD (Postdoctoral Fellow), Karl Lewis (Postdoctoral Fellow), Kyung Shin Kang, PhD (Postdoctoral Fellow), Whitney Bullock, MS (PhD candidate), April Hoggatt (lab manager, senior technician), and Dan Horan (senior technician).