Bone cell biology & disease

There are many diseases that affect the skeleton: these range from common conditions like osteoporosis through to rare bone diseases like osteogenesis imperfecta. Unfortunately, even though we have therapies that can treat the symptoms of bone diseases, there are no cures that can give a patient a healthy skeleton. But we have hope! While it may seem that our bones are unchanging, the skeleton is constantly being renewed so it can adapt to changes in diet and activity levels: some cells dissolve old bone and new replacement bony substance is formed by other cells. By discovering the way these cells behave, we will learn ways to control them so that conditions like osteoporosis and osteogenesis imperfecta can be treated, and so that we can find ways to stop cancers of the bone marrow or blood (e.g. leukemias), and cancers spread to bone (e.g. breast cancer).

Research Overview

Bone is a surprisingly dynamic tissue, continually changing its shape and composition in response to physical exercise, diet and other factors. This is controlled by three cell types within the bone tissue – osteoblasts (that form bone), osteoclasts (that destroy bone) and osteocytes (a network of cells that signal to osteoblasts and osteoclasts).

Our research is focussed on understanding the way these cells communicate with each other to control bone health. Understanding these pathways will help us to develop new methods for the treatment of bone and joint diseases including osteoporosis and arthritis, as well as helping us to understand the growth of cancer within bone, particularly breast cancer, prostate cancer and osteosarcoma.

Research Themes

IL-6 / gp130 family cytokines and sex-differences in cortical structure

Our laboratory has defined the mechanisms by which IL-6 family cytokines (including IL-6, IL-11, Oncostatin M, Cardiotrophin-1 and ciliary-neurotrophic factor) influence osteoblasts, osteoclasts and osteocytes. Most recently, we have discovered that these cytokines control the process by which cortical bone (the hard outer shell of the skeleton) forms, and may explain why men have stronger cortical bone than women. In our ongoing work, we are defining which of these cytokines are most important for this process, and how they are controlled in osteocytes by sex-steroid hormones.

Parathyroid hormone-related protein (PTHrP) and bone strength

Our team discovered PTHrP in 1987 and are continuing to discover new things about how this protein influences the function of cells within the skeleton, including osteocytes. We have recently shown that osteocytes produce PTHrP, and use it to control osteocyte differentiation, bone matrix composition, and bone size. Our ongoing work is defining how different regions of this molecule control osteocyte gene expression, and how this molecule affects embryonic and neonatal bone development.

Control of bone mineralisation by osteocytes

The amount of bone in the skeleton is not the only thing that makes it strong. If bone is of poor material quality (e.g. less, or more mineralised than normal), it can be weak, and more likely to break. Through our work on the Eph/Ephrin family of tyrosine kinases, we discovered that this protein is important for osteoblasts and osteocytes to control the way that bone becomes a hardened, mineralized tissue. This work, in collaboration with the Australian Synchrotron, is helping us to discover how bone mineral becomes incorporated into the skeleton in a way that makes it strong.

Student Projects


Publication Highlights

  1. Cortical bone maturation in mice requires SOCS3 suppression of gp130/STAT3 signalling in osteocytes.  Walker EC, Truong K, McGregor NE, Poulton IJ, Isojima T, Gooi JH, Martin TJ, Sims NA. Elife. 2020 May 27;9:e56666. doi: 10.7554/eLife.56666.
  2. Osteoclasts Provide Coupling Signals to Osteoblast Lineage Cells Through Multiple Mechanisms. Sims NA, Martin TJ. Annu Rev Physiol. 2020 Feb 10;82:507-529. doi: 10.1146/annurev-physiol-021119-034425. Epub 2019 Sep 25.
  3. Increased autophagy in EphrinB2-deficient osteocytes is associated with elevated secondary mineralization and brittle bone. Vrahnas C, Blank M, Dite TA, Tatarczuch L, Ansari N, Crimeen-Irwin B, Nguyen H, Forwood MR, Hu Y, Ikegame M, Bambery KR, Petibois C, Mackie EJ, Tobin MJ, Smyth GK, Oakhill JS, Martin TJ, Sims NA. Nat Commun. 2019 Jul 31;10(1):3436. doi: 10.1038/s41467-019-11373-9.
  4. IL-6 exhibits both cis- and trans-signaling in osteocytes and osteoblasts, but only trans-signaling promotes bone formation and osteoclastogenesis. McGregor NE, Murat M, Elango J, Poulton IJ, Walker EC, Crimeen-Irwin B, Ho PWM, Gooi JH, Martin TJ, Sims NA. J Biol Chem. 2019 May 10;294(19):7850-7863. doi: 10.1074/jbc.RA119.008074. Epub 2019 Mar 28.
  5. Autocrine and Paracrine Regulation of the Murine Skeleton by Osteocyte-Derived Parathyroid Hormone-Related Protein. Ansari N, Ho PW, Crimeen-Irwin B, Poulton IJ, Brunt AR, Forwood MR, Divieti Pajevic P, Gooi JH, Martin TJ, Sims NA. Journal of Bone and Mineral Research. 2018 Jan;33(1):137-153. doi: 10.1002/jbmr.3291.
  6. Bone corticalization requires local SOCS3 activity and is promoted by androgen action via interleukin-6. Cho DC, Brennan HJ, Johnson RW, Poulton IJ, Gooi JH, Tonkin BA, McGregor NE, Walker EC, Handelsman DJ, Martin TJ, Sims NA. Nature Communications. 2017 Oct 9;8(1):806. doi: 10.1038/s41467-017-00920-x.
  7. Anabolic action of parathyroid hormone (PTH) does not compromise bone matrix mineral composition or maturation. Vrahnas C, Pearson TA, Brunt AR, Forwood MR, Bambery KR, Tobin MJ, Martin TJ, Sims NA. Bone. 2016 Dec;93:146-154. doi: 10.1016/j.bone.2016.09.022.
  8. Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass. Walker EC, Johnson RW, Hu Y, Brennan HJ, Poulton IJ, Zhang JG, Jenkins BJ, Smyth GK, Nicola NA, Sims NA. Journal of Biological Chemistry. 2016 Oct 7;291(41):21703-21716.
  9. Cell-specific paracrine actions of IL-6 family cytokines from bone, marrow and muscle that control bone formation and resorption. Sims NA. International Journal of Biochemistry and Cell Biology. 2016 Oct;79:14-23. doi: 10.1016/j.biocel.2016.08.003. Review.
  10. Chondrocytic ephrin B2 promotes cartilage destruction by osteoclasts in endochondral ossification. Tonna S, Poulton IJ, Taykar F, Ho PW, Tonkin B, Crimeen-Irwin B, Tatarczuch L, McGregor NE, Mackie EJ, Martin TJ, Sims NA. Development. 2016 Feb 15;143(4):648-57. doi: 10.1242/dev.125625. Epub 2016 Jan 11.
  11. Quantifying the osteocyte network in the human skeleton. Buenzli PR, Sims NA. Bone. 2015 Jun;75:144-50. doi: 10.1016/j.bone.2015.02.016.
  12. Isolation and gene expression of haematopoietic-cell-free preparations of highly purified murine osteocytes. Chia LY, Walsh NC, Martin TJ, Sims NA. Bone. 2015 Mar;72:34-42. doi: 10.1016/j.bone.2014.11.005. Epub 2014 Nov 15.
  13. EphrinB2 signaling in osteoblasts promotes bone mineralization by preventing apoptosis. Tonna S, Takyar FM, Vrahnas C, Crimeen-Irwin B, Ho PW, Poulton IJ, Brennan HJ, McGregor NE, Allan EH, Nguyen H, Forwood MR, Tatarczuch L, Mackie EJ, Martin TJ, Sims NA. FASEB Journal. 2014 Oct;28(10):4482-96. doi: 10.1096/fj.14-254300. Epub 2014 Jun 30.
  14. The primary function of gp130 signaling in osteoblasts is to maintain bone formation and strength, rather than promote osteoclast formation. Johnson RW, Brennan HJ, Vrahnas C, Poulton IJ, McGregor NE, Standal T, Walker EC, Koh TT, Nguyen H, Walsh NC, Forwood MR, Martin TJ, Sims NA. Journal of Bone and Mineral Research. 2014 Jun;29(6):1492-505. doi: 10.1002/jbmr.2159.