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Is calcium a link between inflammatory bone resorption and heart disease?
1Department of Orthopaedic Surgery and Rehabilitation, The University of Texas Medical Branch at Galveston, Galveston, United States.
Insights
Chronic inflammation increases heart disease risk. Children’s calcium regulation protects against this, unlike adults, potentially preventing cardiovascular disease.
Area of Science:
- Cardiovascular Disease and Inflammation
- Endocrinology and Bone Metabolism
Background:
- Bone-resorbing chronic inflammatory conditions, such as osteoporosis and rheumatoid arthritis, are linked to increased atherosclerotic heart disease risk.
- Anti-resorptive agents have shown reduced mortality in various clinical settings.
- Burn patients reveal age-dependent mechanisms in calcium regulation during inflammation.
Purpose of the Study:
- To investigate the role of calcium regulation via the calcium-sensing receptor (CaSR) in mediating the relationship between chronic inflammation and cardiovascular disease risk.
- To explore age-related differences in CaSR response to inflammatory cytokines.
Main Methods:
- Epidemiologic study analysis.
- Clinical observation in burn patients (children and adolescents).
- Comparative analysis of CaSR responsiveness in children versus adults with chronic inflammatory conditions.
Main Results:
- Children and adolescents exhibit a protective mechanism: pro-inflammatory cytokines up-regulate the parathyroid calcium-sensing receptor (CaSR), leading to hypocalcemic hypoparathyroidism and hypercalciuria.
- This CaSR responsiveness in youth may mitigate cardiovascular morbidity and mortality by limiting extracellular calcium.
- Adults with chronic inflammatory conditions lose this CaSR responsiveness, allowing circulating calcium to promote coronary artery calcification and cardiovascular disease.
Conclusions:
- Age-dependent regulation of CaSR by inflammatory cytokines is a critical factor in cardiovascular risk associated with chronic inflammation.
- The loss of CaSR responsiveness in adults contributes to the development of atherosclerotic heart disease.
- Targeting CaSR pathways may offer novel therapeutic strategies for preventing cardiovascular complications in chronic inflammatory diseases.
Abstract:
Several epidemiologic studies associate bone-resorbing chronic inflammatory conditions with increased risk of atherosclerotic heart disease. These include post-menopausal osteoporosis, spinal cord injury, rheumatoid arthritis, and osteoarthritis. Additional studies have noted that the use of anti-resorptive agents following hip fracture, during rheumatoid arthritis, and prior to intensive care management have resulted in reduced overall mortality and mortality from cardiovascular disorders. The careful study of burn patients has allowed us to detect that children and adolescents have a mechanism that protects them from the entry of calcium into the circulation following inflammatory bone resorption. That is, they respond to pro-inflammatory cytokines by up-regulating the parathyroid calcium-sensing receptor (CaSR) with consequent development of hypocalcemic hypoparathyroidism and hypercalciuria. As extracellular calcium appears to exacerbate and/or prolong the inflammatory response, this responsiveness of the CaSR to inflammatory cytokines may be the factor that reduces cardiovascular morbidity and mortality. In adults with chronic inflammatory conditions, the ability of the CaSR to respond to pro-inflammatory cytokines is lost, suggesting that the calcium that enters the circulation following inflammatory bone resorption may persist in the circulation, entering the small coronary blood vessels and favoring the formation of coronary artery calcification, inflammation, and consequent cardiovascular disease.
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