Osteocyte Cell Death Research Articles

Evidence for the role of osteocytes in the initiation of targeted remodeling

Microdamage in bone contributes to fractures and acts as a stimulus for bone remodeling. Osteocytes are the most abundant cells in bone, and their death by microdamage has been suggested to be the major event leading in the initiation of osteoclastic bone resorption. Even though there is increasing evidence that osteocyte density, microcracks and targeted remodeling are related, there still exist several questions. For example, how osteoclasts are targeted to the specific site of microdamage for repair. It has been proposed that apoptotic osteocytes could secrete a specific signal to target osteoclasts. The other question is the nature of this signal. To elucidate the role of microdamage-induced osteocyte cell death in the initiation of targeted remodelling, this paper discusses the potential use of an in vitro model, in which osteocytes can be three-dimensionally cultured and locally damaged. Furthermore, the method enables one to study the osteocyte-derived soluble interactions with bone marrow cells. It was demonstrated that damaged osteocytes locally affect osteoclast precursors by secreting osteoclastogenic factors, and thus can have a role in the initiation of resorption in bone remodelling. This strongly supports the idea that damage to osteocyte cellular network has the potential to stimulate osteoclastic proliferation and therefore the activation of Basic Multicellular Units (BMUs).

Modeling the thermal conditions around sites of microwave drilling in bone

4704 Citation: Journal of Biomechanics 2006; Vol. 39 Suppl. 1, page S382 Modeling the thermal conditions around sites of microwave drilling in bone R.R. Mann1, O. Aktushev2, A. Gefen1, E. Jerby2 1 Depts. of Biomedical Engineering and 2 Physical Electronics, Tel Aviv University, Israel A new method for orthopaedic drilling was developed, based on microwave energy that is localized at a ``hot spot'' to penetrate bone tissue [1,2]. However, the heat generated during microwave drilling was shown to cause some tissue carbonization and collagen denaturation in vitro [2]. The goal of this study was to develop a model of time-dependent temperature distribution around the drilling site, in order to optimize the drilling process. A finite-difference time-domain (FDTD) model [3] was employed. The model calculates the temperature fields around the drilling site for a given drill bit diameter, microwave drilling power, and bone geometry (e.g. cortical thickness and presence of underlying marrow). The model allows determination of the size of tissue regions exceeding critical temperature and the time exposure to temperature. Generally, we found that the radius and depth of bone that exceeded a 50°C threshold (for osteocyte cell death) increased with the drilling depth, and damage area was wider when bone marrow was considered. Overall, the model emerged as an essential engineering tool for improving the technology and design of orthopaedic microwave drills. Reference: 1. Jerby E., Dikhtyar V., Aktushev O., Groslick U. The microwave drill. Science 2002; 298: 587-589. 2. Eshet Y., Mann R.R., Anaton A., Yacoby T., Gefen A., Jerby E. Microwave drilling of bones. IEEE Transactions on Biomedical Engineering, accepted for publication. 3. Jerby E., Aktushev O., Dikhtyar V. Theoretical analysis of the microwave-drill near-field localized heating effect. Journal of Applied Physics 2004; 97: 034909.

CD40 Ligand Blocks Apoptosis Induced by Tumor Necrosis Factor α, Glucocorticoids, and Etoposide in Osteoblasts and the Osteocyte-Like Cell Line Murine Long Bone Osteocyte-Y4

During characterization of the osteocyte-like murine long bone osteocyte-Y4 (MLO-Y4) cell line, comparison was made with antigen-presenting cells of the immune system known as dendritic cells. It was observed that the MLO-Y4 osteocyte-like cells express CD40 antigen and MHC class I antigen, but they are negative for a series of other dendritic cells markers (DEC-205, CD11b, CD11c, CD86, and MHC class II) and immune cell markers [CD45, CD3, CD4, B220, Gr-1, and CD40 ligand (CD40L)]. RT-PCR results showed expression of CD40 mRNA and lack of CD40L mRNA expression. Like MLO-Y4 osteocyte cells, both primary osteoblasts and the osteoblast-like cell lines MC3T3, OCT-1, and 2T3 were shown to express CD40 antigen by fluorescence-activated cell sorting. Because CD40L has been shown to function as an antiapoptotic factor in dendritic cells, it was reasoned that this molecule may have a similar function in bone cells. In three different assays for apoptosis, including trypan blue exclusion, changes in nuclear morphology, and fluorescence-activated cell sorting staining for annexin V/propidium iodide, CD40L significantly inhibited apoptosis of MLO-Y4 cells induced by dexamethasone, TNF alpha, or etoposide. CD40L also inhibited dexamethasone and TNF alpha-induced apoptosis in the osteoblast cell lines, OCT1 and MC3T3-E1. These data support the hypothesis that CD40L preserves viability of osteoblasts and osteocytes against a wide variety of apoptotic factors independent of signaling or transcriptional mechanisms. Because osteocyte cell death appears to result in bone loss, these studies have important implications for the treatment of bone loss due to glucocorticoid excess and/or to osteoporosis in general.