The etiology of generalized osteoporosis in rheumatoid arthitis

Patients with Rheumatoid Arthritis (RA) not only suffer from painfully inflamed
joints and localized bone loss around these joints, but also lose bone mass
throughout their skeleton (generalized osteoporosis). This generalized bone
loss is associated with an increased incidence of vertebral and hip fractures,
which can result in long-lasting morbidity and even death. Inflammatory
mediators produced by cells around the inflamed joints are known to contribute
to bone loss around the affected joints. The same inflammatory mediators may
also contribute to the etiology of generalized osteoporosis, since these
mediators are able to enter the bloodstream of RA patients thereby reaching
bone cells in remote areas.

The main hypothesis is that circulating inflammatory mediators are the main
causative factor for the emergence of generalized osteoporosis in patients with
Rheumatoid Arthritis (RA).

1.Does the serum of patients with active RA, containing inflammatory-mediators,
affect the formation and/or function of osteoblasts, osteocytes, in vitro?

2.Which pro-inflammatory mediators are expressed in serum derived from patients
with active RA and in serum derived from healthy controls?

3.How do the pro-inflammatory mediators identified under *2*, affect the
formation and/or function of osteoblasts and/or osteocytes in vitro?

Whether circulating proinflammatory mediators, as present in patients with RA,
affect osteoblast formation and/or function will be studied by culturing
osteoblasts derived from 20 healthy donors in the presence of serum from RA
patients or from age and gender-matched healthy control subjects. Primary bone
cell cultures will be used as a model for osteoblasts (25), Osteoblast
proliferation will be measured using proliferation assays and quantification of
Proliferating Cell Nuclear Antigen. Differentiation of (pre)osteoblasts towards
mature osteoblasts and osteocytes will be measured using alkaline phosphatase
activity assays and real time PCR techniques. Osteoblast function will be
determined by performing in vitro bone formation assays.

Which pro-inflammatory mediators are expressed in serum derived from patients
with active RA in comparison to serum derived from healthy controls will also
be investigated. Analysis of the inflammation profiles will be performed using
a macro protein array technique. This innovative technique will be used to
detect differentially expressed inflammatory mediators associated with
impairment of osteoblastic function.

Although prevention of osteoporosis in RA patients is extremely important,
patients will not directly experience the benefits. However, if patients can
avoid fractures, this will have direct impact on their quality of life. The
possibility to live independently longer is one of the major demands of all
older people and this will not be different in RA patients.

Since osteoporosis is more common in patients with RA than in healthy controls
these patients suffer more often from fractures. The consequences of
osteoporotic fractures are dramatic and include pain, decreased quality of
life, disability, loss of independence and mortality. Prevention of
osteoporosis and especially fractures has many benefits including: pain
reduction, improvement of quality of life and most important a longer,
independent life.