Biochemical Toxicology of Osteoporosis: Mechanisms of Cadmium-Induced Bone Loss

Maryka Bhattacharyya Senior Biochemist Bldg: 202. Room: B 313 E-mail: mhbhatt@anl.gov Phone: (630) 252-3923   Biographical Sketch Publications Posters: PDF1, PDF2

> Research

The long-term objectives of this research program are to determine the mechanism by which cadmium causes bone loss and to relate these findings to human exposures.  Our experiments are based on the hypothesis that 1) Cd can act directly on bone cells or their precursors, and 2) these bone effects are separate from any effects Cd may have on other organs (e.g., renal tubules or gastrointestinal tract).  Ultimately we aim to understand the basis for an increased susceptibility of the female skeleton to Cd during periods of pregnancy and lactation (Bh88a) and after removal of the ovaries (to simulate human menopause) (Bh88b).  

Cadmium causes bone loss in experimental animals at blood cadmium concentrations below current OSHA standards for industrial exposure (USOSHA92).  In addition, recent epidemiological studies report a correlation between increased blood cadmium concentration and decreased bone density among humans environmentally and occupationally exposed to cadmium (Ja98, St99, Al00).  Cadmium bound to metallothionein subunit

One in eight Americans is 65 or older.  As our society ages, research into the health problems associated with aging, such as bone loss, is taking center stage.  Osteoporosis is a major cause of disability in elderly persons, with hip fracture often triggering the dreaded transition to a dependent lifestyle.

Cadmium has important uses for coatings for steel; stabilizers for PVC plastics; bright red, orange, and yellow pigments; rechargeable Ni/Cd batteries; strong railway conductor alloys; and solar cells. Cd at 0.2-2 ppm in soil and rice contributed to the etiology of Itai-Itai, a disease characterized by osteoporosis/osteomalacia and kidney dysfunction in Japanese women. Persons who smoke one or more packs of cigarettes per day show mean blood Cd concentrations (2 ug/l) tenfold over those of nonsmokers (about 0.2 ug/l) -- in range of blood concentrations causing bone loss in animals. Cd in cigarettes may be an important cause of osteoporosis in humans. 

In healthy bone, a balance exists between the rates of bone formation and bone resorption.  After skeletal growth has stopped, a new equilibrium is reached that typically results in a slow, age-dependent net loss of bone mineral in humans.  Cadmium can accelerate this net loss of bone mineral, increasing the incidence of osteoporosis in the elderly.  Understanding the contribution of environmental agents such as cadmium to osteoporosis in humans is an important undertaking.

> Description

Multinucleated osteoclast- the cell  that dissolves bone mineral and  collagen matrix

Results of two experiments in our laboratory lay the groundwork for us to investigate specific pathways that may be involved in the bone demineralization response to cadmium.  A gene expression microarray experiment identified genes whose expression change in bone cells early after low level cadmium exposure in mice (Re02a).   Using a second approach to investigate mechanism, we determined whether cadmium could cause decreased bone mineral content in fos-deficient and src-deficient mice, both of which lack functioning osteoclasts (Re02b).

 

The following four results are particularly important to our current specific research aims: 

(1) Genes involved in osteoclast formation/activation appear to be involved in the bone cell response to low level  cadmium;

(2) Cadmium can cause a decrease in bone mineral content via a fos-independent pathway;

(3) p38 MAP kinase appears to be involved in bone cell signaling after cadmium;

(4) Cadmium causes early and strong induction (18-fold) of a gene of unknown function in bone cells.

These and other studies continue to raise the question of the relative contribution of decreased bone formation vs. increased bone resorption in the early bone response to low level cadmium exposure in the whole animal.  

> Goals

(1) On basis of microarray results, determine gene- and protein-level changes involved in bone response to cadmium in mice and bone cells in culture

(2) Investigate basis for significant bone mineral decrease in cadmium-exposed fos-deficient mice

(3) Determine sequence of full-length mRNA, tissue-dependent expression, and potential function of gene encoding unknown protein that is highly induced (18-fold) by cadmium in bone cells

(4) Determine contribution of decreased bone formation vs. increased osteoclast-mediated bone resorption in bone response to cadmium in mice