Cellular and Molecular Toxicity of Lead in Bone

Abstract

To fully understand the significance of bone as a target tissue of lead toxicity, as well as a reservoir of systemic lead, it is necessary to define the effects of lead on the cellular components of bone. Skeletal development and the regulation of skeletal mass are ultimately determined by the four different types of cells: osteoblasts, lining cells, osteoclasts, and osteocytes. These cells, which line and penetrate the mineralized matrix, are responsible for matrix formation, mineralization, and bone resorption, under the control of both systemic and local factors. Systemic components of regulation include parathyroid hormone, 1,25-dihydroxyvitamin D3, and calcitonin; local regulators include numerous cytokines and growth factors. Lead intoxication directly and indirectly alters many aspects of bone cell function. First, lead may indirectly alter bone cell function through changes in the circulating levels of those hormones, particularly 1,25-dihydroxyvitamin D3, which modulate bone cell function. These hormonal changes have been well established in clinical studies, although the functional significance remains to be established. Second, lead may directly alter bone cell function by perturbing the ability of bone cells to respond to hormonal regulation. For example, the 1,25-dihydroxyvitamin D3-stimulated synthesis of osteocalcin, a calcium-binding protein synthesized by osteoblastic bone cells, is inhibited by low levels of lead. Impaired osteocalcin production may inhibit new bone formation, as well as the functional coupling of osteoblasts and osteoclasts. Third, lead may impair the ability of cells to synthesize or secrete other components of the bone matrix, such as collagen or bone sialoproteins (osteopontin). Finally, lead may directly effect or substitute for calcium in the active sites of the calcium messenger system, resulting in loss of physiological regulation. The effects of lead on the recruitment and differentiation of bone cells remains to be established. Compartmental analysis indicates that the kinetic distribution and behavior of intracellular lead in osteoblasts and osteoclasts is similar to several other cell types. Many of the toxic effects of lead on bone cell function may be produced by perturbation of the calcium and cAMP messenger systems in these cells.

Lack of reversal of oxidative damage in renal tissues of lead acetate‐treated rats

“…During exposure to Lead, the heavy metal usually distributes into the hard tissues like bone and teeth, where it accumulates, only to result in a sustained release and maintenance of unacceptable blood lead levels, long after the exposure period (Pounds et al, ). The fresh release of lead following its withdrawal from the rats in this study from body stores may be responsible for the decreases in the antioxidant enzyme activities observed after the withdrawal period (Haleagrahara et al, ).…”

Prevalence of elevated blood lead levels in nigerian children

“…The diet in Nigeria is lacking in calcium, 27 and children may be preferentially absorbing another divalent cation—lead—in lieu of calcium. 28 Lead has been found in breast milk in Nigeria. 29 …”

Whole blood lead levels are associated with radiographic and symptomatic knee osteoarthritis: a cross-sectional analysis in the Johnston County Osteoarthritis Project

“…Pb interferes with regulatory aspects of bone cellular function and matrix synthesis, with effects on dietary calcium uptake and metabolism and conversion of vitamin D to 1,25-OH vitamin D [23,27,28]. Pb exposure affects the function of bone remodeling cells, causing impaired collagen synthesis by osteoblasts and impaired resorptive capacity of osteoclasts [28].…”

“…Pb interferes with regulatory aspects of bone cellular function and matrix synthesis, with effects on dietary calcium uptake and metabolism and conversion of vitamin D to 1,25-OH vitamin D [23,27,28]. Pb exposure affects the function of bone remodeling cells, causing impaired collagen synthesis by osteoblasts and impaired resorptive capacity of osteoclasts [28]. In a study of bone samples from individuals without known bone disease or Pb exposure, researchers identified marked accumulation of Pb specifically at the cartilage tidemark, which is the transition point between the calcified and noncalcified cartilaginous matrix [29], where clefts occur as OA develops.…”