Research group - Tuomas Näreoja
Our work in bone biology is aimed to understand development of bones, signaling in bone cells and develop diagnostics for bone related diseases.
Presently my lab’s research builds on three interconnected cornerstones: 1. Further development of an in vitro model of bone, 2. Fundamental cell biology of osteoclasts and 3. Development of serological diagnostics for main complications affecting prosthetic implants which if left unchecked, cause dissolution of bone, inflammatory periprosthetic osteolysis and periprosthetic joint infections.
Theme 1 - 3D in vitro model of bone:
Bone remodeling is a constantly undergoing process where bone resorbing osteoclasts, osteocytes inhabiting channels inside bone and bone mineralizing osteoblasts work together in order to heal damage and remake the skeleton, respond to mechanical stimulus and adapt bone structure to environmental factors and maintain Ca2+ and phosphate homeostasis. These cells receive regulatory signals through hormonal signaling network and transmit information to each other directly with cell-cell contacts, with soluble ligands as well as through surrounding extracellular matrix.
In the in vitro model of bone combines osteocytes, osteoblasts and osteoclast to a co-culture within relevant 3D extracellular matrix. The model facilitates biomarker discovery for inflammatory osteolysis without interference from other organ systems and identification druggable targets in inflammatory signaling.
Theme 2 - Molecular mechanisms in inflammatory osteolysis:
Classical osteoclasts differentiate from monocytes upon stimulation with receptor activator of nuclear factor-κB ligand (RANKL). Recent years have provided evidence of inflammatory osteoclast population that would be capable of both resorption and proinflammatory signaling, an environment with TNF-α and IL-6. Periprosthetic osteolysis is considered to be caused by a response to foreign material, especially wear debris from the prosthetics that activates macrophages. Phagocytosis of microscale debris activates macrophages and they in turn release mediators of damage associated molecular pattern that includes at least prostaglandin E2, TNF-α, IL-1β and IL-6. These cytokines induce accumulation of monocytes in periprosthetic tissue and increase of RANKL expression by macrophages, giant cells and fibroblasts. In periprosthetic tissue IL-4 and IL-13 induce activation of M2a-type macrophages that form foreign body giant cells (FBGC). FBGCs observed on bone implants have been demonstrated to lack resorptive ability, but have an ability to promote inflammation, hence, their presence is indicative of implant failure.
We aim to elucidate processes controlling osteoclast differentiation and identify the points where the classical differentiation diverges into development of inflammatory osteoclasts and foreign body giant cells, and are there ways to prevent such differentiation.
Theme 3 - Diagnostics:
Total hip arthroplasty (THA) is a quality of life restoring surgical procedure in orthopedics and annually more than 2 million patients undergo THA worldwide. However, more than 100000 patients annually have to undergo a risky and costly revision surgery due to periprosthetic osteolysis (PPO) and additionally 25000 more due to periprosthetic joint infections (PJI). This despite continual improvements in surgical technique and implant design. Osteolytic lesions around well-fixed orthopedic implants are notoriously difficult to detect and are, 7–14 years after surgery, present in 10-70 % of hips. Many patients feel discomfort at their hip or knee implants but currently we do not possess means to diagnose what causes the problem. Diagnosis of osteolysis is based on radiographical observations and on movement of the prosthetic implant. In the absence of an early and robust diagnosis treatment is limited to revision surgeries. The primary aim of my research is to provide a serological method to diagnose infections and inflammatory osteolysis related to prosthetics.
Currently revision surgeries are the only available treatment for prothesis-related inflammatory osteolysis and cases with osteolytic lesions are left untreated until implant loosens or a debilitating fracture occurs. Early serological detection and accurate diagnosis of the onset of implant inflammation and osteolysis or any low-virulent infections present will provide a treatment window where the condition can be reversed and no replacement surgery will be necessary
Such treatments would likely include antibiotic, anti-inflammatory and antiresorptive medications. Moreover, with the recent advances with bone anabolic treatments, e.g. anti-sclerostin antibody romosozumab, we have the opportunity to make use a diagnosis in making treatment decisions that have an opportunity to reverse the condition.
Research group leader
Laia Mira Pascual
We are happy to assist postdoctoral applicants who wish to join our group with their grant applications and students wishing to do their M.Sc. thesis work. Please contact: firstname.lastname@example.org.
Cell culture, biochemistry, transcriptomics, high-content imaging, immunoassays, nanoparticles.
Jane and Aatos Erkko foundation
KID-funding for research education at KI
Loo and Hans Osterman foundation
Maud Kuistila memorial foundation
KI research foundation
Study Programme for Biomedical Analysts
In vitro model of bone to facilitate measurement of adhesion forces and super-resolution imaging of osteoclasts.
Deguchi T, Alanne MH, Fazeli E, Fagerlund KM, Pennanen P, Lehenkari P, et al
Sci Rep 2016 Mar;6():22585
Super-sensitive time-resolved fluoroimmunoassay for thyroid-stimulating hormone utilizing europium(III) nanoparticle labels achieved by protein corona stabilization, short binding time, and serum preprocessing.
Näreoja T, Rosenholm JM, Lamminmäki U, Hänninen PE
Anal Bioanal Chem 2017 May;409(13):3407-3416
Ratiometric Sensing and Imaging of Intracellular pH Using Polyethylenimine-Coated Photon Upconversion Nanoprobes.
Näreoja T, Deguchi T, Christ S, Peltomaa R, Prabhakar N, Fazeli E, et al
Anal. Chem. 2017 02;89(3):1501-1508
Actin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane.
Wen PJ, Grenklo S, Arpino G, Tan X, Liao HS, Heureaux J, et al
Nat Commun 2016 08;7():12604