Bone resorption

Résumé

Bone resorption is resorption of bone tissue, that is, the process by which osteoclasts break down the tissue in bones and release the minerals, resulting in a transfer of calcium from bone tissue to the blood. The osteoclasts are multi-nucleated cells that contain numerous mitochondria and lysosomes. These are the cells responsible for the resorption of bone. Osteoblasts are generally present on the outer layer of bone, just beneath the periosteum. Attachment of the osteoclast to the osteon begins the process. The osteoclast then induces an infolding of its cell membrane and secretes collagenase and other enzymes important in the resorption process. High levels of calcium, magnesium, phosphate and products of collagen will be released into the extracellular fluid as the osteoclasts tunnel into the mineralized bone. Osteoclasts are prominent in the tissue destruction found in psoriatic arthritis and rheumatological disorders. The human body is in a constant state of bone remodeling.

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https://en.wikipedia.org/wiki/Bone_resorption

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T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway

Zhen Chen, Mario Michael Zaiss

Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.

Amer Assoc Advancement Science2014

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Characterization of bone progenitor cells after GFP lentivirus transfection

Tanja Cloé Hausherr, Axelle Deirdre Eve Justafré

Several treatments have been developed for treating bone fractures as they are very common events. Amongst other new strategies, synthetic bone substitutes present a very high potential therapy because they lower the risk of infection and rejection. Moreover, bone progenitor cells have been added to these bone graft substitutes, allowing them to gain the property of osteogenesis. Surprisingly, it has been observed that bone formation was less efficient in the case of bone substitutes seeded with bone progenitor cells compared to cell-free bone substitutes. This result raised questions about the evolution of these cells inside the implant. In order to investigate this shortcoming, osteoprogenitor cells have been transfected using a GFP lentivirus. Using a viability assay and Alizarin and ALP stainings, the characterization of GFP-transfected bone progenitor cells demonstrated a phenotype unaltered after transfection with a lentivirus.

2015

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Total Hip Replacement (THR) is today a routine procedure executed more than 800'000 times per year worldwide. THR gives generally satisfactory results, although the quality of outcome is inversely proportional to the age of the patient. In parallel, there is a trend to propose cementless THR to patients younger than 60 years. These patients have more demanding physical activity resulting in a significant increased failure rate of the implants. In particular for these patients, the desired service life of the implant should be extended. Proximal peri-implant bone loss is generally observed during the first two years following the implantation. This bone loss may lead to aseptic loosening, the major cause of THR failure. In order to control peri-implant bone remodeling and in particular the proximal bone loss, we developed the innovative concept of using the orthopedic implant as drug delivery system (DDS). The cementless stem of a hip implant would be coated with hydroxyapatite (HA) and bisphosphonate, a drug affecting bone resorption. The basic idea is to biologically reduce the initial peri-implant bone loss by decreasing the osteoclastic bone resorption activity. This approach could significantly increase the THR outcome. Pre-clinical tests were performed to numerically validate this new concept. An existing bone remodeling model was modified to take into account the bisphosphonate effect. The outcome of a THR was evaluated with different simulated bisphosphonate concentrations. Results of the simulations showed that the implant used as a drug delivery system would increase bone density around the implant and decrease, at the same time, the micromovements between the implant and the surrounding bone tissue. Therefore, the evolution towards peri-implant bone loss and fibrous tissue development at the bone-implant interface would be delayed, which could positively influence the THR outcome. Pre-clinical tests allowed us to verify that a partial proximal coating of the stem would result in a homogeneous bone remodeling, a situation biomechanically more favorable than the simulated situation obtained with a full coating of the stem. Despite a numerically observed positive concentration effect, it was noted that the decrease of peri-implant bone loss was most notably affected with the intermediate simulated bisphosphonate concentration. Based on these positive pre-clinical results, in vitro and in vivo experiments were performed to further validate the concept of orthopedic implant used as drug delivery system. As bisphosphonates were developed for systemic delivery, little information was available regarding the bisphosphonate concentrations which could be safely used for a local delivery application. It was especially important to quantify the bisphosphonate concentration osteoblasts could be exposed to without harmful effect for the bone formation process. We challenged osteoblasts from human and murine origins to different concentrations of the choosen bisphosphonate (Zoledronate from Novartis). As wear particles are inevitably present in the peri-implant bone, we also added titanium particles to quantify the eventual synergetic negative effect between Zoledronate and particles on osteoblast behavior. In this in vitro study, we showed that Zoledronate did not impair proliferation of human osteoblasts when used at concentrations lower or equal to 1 µM, while murine cells could be exposed to concentrations up to 10 µM. A concentration of 0.01% of titanium particles did not impair proliferation of either cell line. Zoledronate affected, through a chelation phenomenon, ALP activity of murine osteoblasts, whereas the presence of titanium particles strongly decreased the ALP activity of murine osteoblasts. We did not detect any synergic effect of Zoledronate and titanium particles on neither human and murine osteoblast behavior. Those results allowed us to conclude that 1 µM and 10 µM Zoledronate concentrations for human and murine respectively, could be used in the proposed drug delivery system. The basic idea behind the drug delivery system is that the bisphosphonate will stay around the implant where its effect on bone resorption is needed. Since the drug is directly brought into contact with the endosteal bone, it was necessary to study the bisphosphonate diffusion in bone. The in vitro measured Zoledronate diffusion profile in the bone showed that the bisphosphonate entered the bone and diffused from the endosteal bone towards the periosteal bone. The drug accumulated in the first millimeter of the endosteal bone. This meant that the Zoledronate would stay in the peri-implant bone and would not reach regions which are not influenced by the presence of the implant. Based on the in vitro results for Zoledronate concentrations effect on osteoblast and diffusion in bone, an in vivo experiment was designed to demonstrate the proof of concept of orthopedic implant used as drug delivery system. Several Zoledronate quantites were grafted to hydroxyapatite (HA) coatings of titanium implants. The implants were inserted in rat condyles for 3 weeks. Bone density, histomorphometric and biomechanical measurements were performed on the collected rat femurs. A concentration-dependent effect was observed on the peri-implant bone density and on different histomorphometric parameters. The Zoledronate coated implant positively influenced the structure of the trabecular bone. Biomechanical pull-out tests confirmed the higher peri-implant bone quality of Zoledronate coated implant. Interestingly, this in vivo study highlighted the existence of a window of Zoledronate coating concentration in which the mechanical fixation of the implant was increased. A similar result was suggested with the pre-clinical testing. The in vivo study allowed the demonstration of proof-of-concept for orthopedic implant used as drug delivery system to control peri-implant bone remodeling. The results obtained in this thesis might then open the way of an easy transformation of currently existing HA coated implants. By grafting bisphosphonate onto the implant HA coating, the peri-implant bone loss might be reduced which would increase the service life of a THR. This approach is especially interesting for patient younger than 60 years.

EPFL2004

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EPFL2004