Barbieri Thesis - BioMedical Materials program (BMM)

Chapter 1 – Introduction
Key concept box 2
Instructive signalling in bone tissue self–regeneration (or bone remodeling).
Osteocytes are able to perceive mechanical pressures and loads acting at the surface of bone. [32–35]
It is hypothesized that such external stimuli induce interstitial fluid flow along the canaliculi, and
consequently provoke shear stresses that deform the osteocyte membrane. [36, 37] In response to
these stimuli, osteocytes modulate the secretion of many molecules, e.g. insulin–like growth factors
(IGF), osteocalcin, sclerostin, nitric oxide, RANKL, TNF–related cytokines and osteoclasts
differentiation factors (ODF). Such molecules are transported by interstitial fluids towards the bone
surface, where they influence on the cellular activity of surface cells, i.e. osteoblasts and osteoclasts,
triggering bone remodeling (i.e. paracrine effect). [34–37] Through this process, osteocytes allow bone
tissue adapting to external mechanical stresses by inducing osteoblasts to synthesize new bone
matrix when there are increased loads, or inducing osteoclasts resorbing tissue when there is a
decreased use of the bone. [34–37] Other physical triggers for remodeling are the micro–cracks that
form in bone tissue due to continuous stresses during life. [137, 138] In such scenario, osteocyte
apoptosis occurs in proximity of the cracks. [139–141] It is believed that dying cells send signals to the
surrounding healthy osteocytes, which later secrete the aforementioned signaling molecules and
influence on the surface cells that are triggered to repair the crack. [140, 141]
In the 1990s, gene therapy was proposed as an exciting and novel approach aiming
to transfer genetic material or biomolecules (e.g. growth factors) towards one’s target
cells/tissue to cure a disease or improve the patient’s healthy. Gene therapy is based
on the concept of using viruses (i.e. adenoviruses, retroviruses and lentiviruses) as
genetic shuttles for carrying the gene or protein of interest. [85, 142, 143] Depending on the
nature of the viral genome, such vectors can be RNA– or DNA–viral vectors.
Unfortunately, after the death in 1999 of a patient treated for ornithine
transcarbamylase deficiency (i.e. a rare metabolic urea cycle disorder) and other
issues with immunogenicity, carcinogenicity and vector manufacturing many
physicians and scientists lost hope for gene therapy. [144] However recently gene
therapy gained interest again in fields such as ophthalmology, where it appears
promising for the treatment of retinal diseases. [145] Although the ideal genetic delivery
vehicle has not been found, this approach holds lot of potential, especially with
single–gene problems, and therefore is still being actively investigated.
Stem (or differentiated) cells therapy is the process where new cells are introduced
into a damaged site. For this purpose, either stem or differentiated cells are harvested
from the patient and expanded in laboratory. After proliferation, they are injected back
in the patient (i.e. autologous stem cell therapy), either in blood stream or directly in
the injured sites. This strategy may also use, with some risks, cells from different
individuals (i.e. allogeneic stem cell therapy) or embryonic stem cells. Example of
therapies, either clinically used or still under investigation, are the use of bone marrow
stem cells to treat pancreas cancer, [146] and leukemia, [147] and stem cells have been
proposed as possible future therapy to fight Fanconi anemia, a bone marrow failure
syndrome. [148] Currently new applications, such as in neurology and cardiology fields,
are under investigation. [149, 150] However, despite of its potential this technique is not
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