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European Biopharmaceutical Review

Skeletons in the Closet

Ronan Le Bot at Atlantic Bone Screen SAS opens the door on critical research methods that reveal new treatments for bone pathology

Bone tissue is continually being remodelled according to physiological circumstances. Two main cell populations (osteoblasts and osteoclasts) are involved in this process and cellular activities are modulated by hormones, cytokines and growth factors. Within the last 20 years, many factors involved in bone tissue metabolism have been found to be closely related to the inflammatory process. With an ageing population in most countries, bone and mineral disorders – whether of tumour origin or not (metabolism) – are becoming increasingly relevant to every day clinical practice. Consequently, new therapeutic tools are needed from companies specialising in bone tissue.

BONE REMODELLING

Bone is a specialised connective tissue formed by a mineralised matrix that confers its elasticity and strength properties. Bone remodelling allows for adaptation to mechanical constraints and maintains homeostasis of phosphorus and calcium through coordinated phases of formation and resorption. Thus, bone remodelling involves synthesis of organic matrix by osteoblasts and bone resorption by osteoclasts. Osteoblasts differentiate from mesenchymal stem cells through a series of progenitor stages to form mature matrix-secreting osteoblasts that are progressively transformed into osteocytes. Osteoblasts and osteocytes connected by gap junctions then constitute a cellular network, both on the bone surface and within the bone matrix. Osteoclasts are the main protagonists of bone resorption. If they are haematopoietic in origin and are closely related to macrophages, they also possess several characteristic features (multinucleation, highly polarised morphology and numerous mitochondria).

Osteoclasts resorb bone by attaching to the surface, then secreting protons into an extracellular compartment formed under their ruffled border. This secretion is necessary for bone mineral solubilisation leading to the acidification of this compartment and allows the digestion of the organic matrix by acid proteases (1). The other cell protagonists present in the bone microenvironment (monocytes/macrophages, lymphocytes and endothelial cells) also contribute to bone remodelling by direct contact with bone cells or by the release of soluble effectors. The study of the molecular and cellular protagonists involved in these interactions allow for a better understanding of the associated pathology.

The interactions between osteoblasts and osteoclasts are tightly regulated by physical parameters (mechanical stimulation, for example) and numerous polypeptides (hormones, cytokines) (2). Any disturbance between these effectors disturbs this equilibrium and leads to the development of skeletal abnormalities, characterised by decreased (osteoporosis) or increased (osteopetrosis) bone mass. Increased osteoclast activity is observed in many osteopathic disorders including post-menopausal osteoporosis, Paget’s disease, primary bone tumours, lytic bone metastases, multiple myeloma and rheumatoid arthritis, leading to increased bone resorption and a loss of bone mass. Osteoblasts control bone-resorbing activities of osteoclasts and are also clearly involved in osteoclast differentiation.

BONE TUMOUR AND BONE METASTASES

The invasion of bone tissue by a benign or malignant tumour (primary or secondary) rapidly affects the balance between bone resorption and apposition. In some rare cases, tumour development leads to osteoformation associated with weak osteolysis, as in some forms of osteosarcoma or osteoblastic metastasis predominating in patients with prostatic adenocarcinoma. In most cases, the skeletal manifestation of malignancy is focal osteolysis. This imbalance in favour of bone resorption can result from the acquisition of new cellular properties by bone cells – an increase in the proteolytic activity or alteration in local or humoral factors expression. One hypothesis is that genomic instability of tumour cells (bone metastases, bone sarcoma, giant cell tumours) might cause mutations that affect critical cellular properties. Another hypothesis is the importance of the microenvironment which favours bone resorption.


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Ronan Le Bot is the founder and CEO of Atlantic Bone Screen company. He graduated as a Pharmacist at the University of Nantes (France) and obtained his Degree of Preclinical Expertise from the University of Nancy (France). After several months spent in the pharmaceutical industry at Aventis Pharma, he joined the Pathophysiology of Bone Resorption and Therapy of Primary Bone Tumours laboratory of the Medicine Faculty of Nantes, and created the Atlantic Bone Screen company in October 2005.
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