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.

Relationship between low blood lead levels and growth in children of white-collar civil servants in Korea

“…Lowlevel exposure to lead rarely causes a unique disease or pathological lesion, but contributes to loss of organ function (Pounds et al, 1991). The effects of lead may result from two processes: (1) influences on the endocrine organs that synthesize or produce hormones affecting bone growth and (2) altered bone cell functions, such as cell division, enzyme function, or malfunction of the calcium messenger system.…”

Allogeneic and Autogenous Bone Grafts Are Affected by Historical Donor Environmental Exposure

“…Limited data on bone graft supplements and osteotoxicity of lead should not be taken to mean that there are no published data. Population-based studies, animal studies, and cellular studies have found evidence of problematic effects of lead at the levels reported in a proportion of specimens in both screened and unscreened groups of specimens in this study [5,6,12,18,20]. Understanding the role of screening for higher concentrations of lead composition incommercially available bone graft materials and potential benefits with regard to reduced nonunion or pseudoarthrosis requires further study.…”

“…Lead has been shown to have deleterious effects on bone formation and cellular remodeling at concentrations as low as 2 parts per million [6,18,20]. In children, exposure results in impairment in skeletal development, reduced chest circumference, diminished stature, and can be assessed with blood tests for markers of bone turnover in this population [5,6,[10][11][12].…”

“…In children, exposure results in impairment in skeletal development, reduced chest circumference, diminished stature, and can be assessed with blood tests for markers of bone turnover in this population [5,6,[10][11][12]. The mechanism and toxicology of lead in bone formation, resorption, and healingis well known being mediated by impairment of the cellular pathways regulating osteoblast and osteoclast function [3,4,6,8,15,16,18,20,22]. Presumably the levels of lead in allografts mirror the level of lead in bone in the general population; however, the degree to which processing might decrease this and the frequency with which potentially osteotoxic levels appear in bone grafts have not been studied.…”

Retained Bullet Removal in Civilian Pelvis and Extremity Gunshot Injuries: A Systematic Review

“…Previous studies in animals have shown that bone lead levels significantly affect bone healing [3]. Several authors have shown the adverse effects of lead on bone formation and resorption by demonstrating its impact on osteoblast and osteoclast activity [6,14,17,20,26,27]. One such study investigated the response bone lead levels exhibited on tibial fractures treated with intramedullary fixation in mice [3].…”