epidermal-growth-factor and Osteitis-Deformans

Valosin containing protein (VCP) disease (also known as Inclusion Body Myopathy, Paget Disease of Bone and Frontotemporal Dementia [IBMPFD] syndrome) is caused by mutations in the gene encoding VCP classically affecting the muscle, bone and brain. Although the genetic cause has been identified, details regarding the pathogenesis of IBMPFD have not been fully determined. Muscle wasting observed in VCP disease is suggestive of cytokine imbalance. We hypothesized that dysfunctional protein homeostasis caused by VCP mutations leads to cytokine imbalances thereby contributing to the muscle wasting phenotype. Circulating levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF a) and epidermal growth factor (EGF) were measured in plasma of patients with VCP disease or controls. TNF a and EGF were significantly altered in VCP disease as compared to control. TNF a was up-regulated, consistent with a cachexia phenotype and EGF levels were increased. No significant differences were observed in IL-4 and IL-6. Cytokine imbalances may be associated with VCP disease and may play a contributory role in VCP myopathy. Further understanding of how VCP dysfunction leads to aberrant protein homeostasis and subsequent cytokine imbalances may also aid in the understanding of other proteinopathies and in the development of novel treatments.

Topics: Adenosine Triphosphatases; Case-Control Studies; Cell Cycle Proteins; Cytokines; Epidermal Growth Factor; Frontotemporal Dementia; Humans; Interleukin-4; Interleukin-6; Muscle Development; Muscular Atrophy; Muscular Dystrophies, Limb-Girdle; Mutation; Myositis, Inclusion Body; Osteitis Deformans; Signal Transduction; Syndrome; Tumor Necrosis Factor-alpha; Valosin Containing Protein

Human osteoclasts are well characterized multinucleated cells whose function is the directed resorption of normal bone (NB). Osteoclastic bone destruction accompanies lytic solid tumors and myeloma as well as Paget's disease (PD) of bone and giant cell tumors of bone (GCTB). The mechanism of this stimulation of osteoclastic bone resorption is unknown. This study was designed to detect cytokines present in the multinucleated cells of PD and GCTB in order to determine whether cytokine abnormalities exist to account for bone lysis. Nine cytokines, representing the functions of bone resorption, angiogenesis, tumor necrosis, bone cell proliferation, and osteoblast-osteoclast coupling, were examined by immunohistochemistry using tissue samples from 15 NB, 17 PD, and 19 GCTB patients. Standard nonparametric statistical analysis showed a significant increase (P < 0.01 to 0.05) in immunostaining between osteoclasts of PD and NB for interleukin-6 (Il-6), tumor necrosis factor beta (TNFbeta), epidermal growth factor (EGF), platelet derived growth factor (PDGF), and basic fibroblast growth factor (bFGF). There was a statistically significant decrease in immunostaining of giant cells of GCTB as compared with NB for transforming growth factor beta (TGFbeta), but no other differences from normal osteoclasts. The increase in staining of PD osteoclasts over the giant cells of GCTB was significant (P < 0.01) for Il-6, TNFbeta, PDGF, bFGF and insulin growth factor-1 (IGF-1), and (P < 0. 05) for Il-1 and EGF. It was concluded that marked cytokine differences exist in vivo between osteoclasts of NB and PD lesions consistent with stimulated resorption. Alternatively, "osteoclastoma" cells in the center of the tumor did not overexpress the cytokines associated with bone lysis, suggesting some other mechanism for stimulated resorption.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Neoplasms; Bone Resorption; Child; Child, Preschool; Cytokines; Epidermal Growth Factor; Female; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Giant Cell Tumor of Bone; Giant Cells; Humans; Insulin-Like Growth Factor I; Interleukin-1; Interleukin-6; Lymphotoxin-alpha; Male; Middle Aged; Osteitis Deformans; Osteoclasts; Platelet-Derived Growth Factor; Transforming Growth Factor beta