BoneKEy-Osteovision | Commentary
The acid test for bone
David A Bushinsky
DOI:10.1138/20040124
Commentary on: Ludwig MG, Vanek M, Guerini D, Gasser JA, Jones CE, Junker U, Hofstetter H, Wolf RM, Seuwen K. Proton-sensing G-protein-coupled receptors. Nature. 2003 Sep 4;425 (6953):93-8.
On a daily basis, cellular metabolism of dietary amino acids in humans leads to the production of approximately 1 mmol/kg of acid (in the form of hydrogen ions, which are also called protons) (). Additional endogenous acid production also occurs during pathophysiological states, such as diarrhea, diabetic ketoacidosis, and lactic acidosis. The subsequent reduction of systemic pH results in the clinical entity of metabolic acidosis. The mammalian physiologic response to metabolic acidosis is to rapidly increase the extracellular fluid pH toward the physiologic neutral of 7.40 to maintain normal cellular function. This integrated homeostatic response to an acid challenge first involves the buffering of the acid, then increasing the respiratory rate to lower the partial pressure of carbon dioxide, and finally the excretion of additional hydrogen ions. The initial step, buffering the additional acid, is the most critical step in the maintenance of neutral pH. The final step, renal excretion of additional hydrogen ions, begins hours after the acid challenge and is complete only days later. Renal acid excretion relies on normal kidney function; as we age, our ability to excrete acid declines, and older individuals become slightly, but significantly, more acidemic compared with younger individuals ().
Bone has long been thought to be involved in the buffering response to systemic acidosis (). In humans with normal renal function, the provision of additional dietary acids results in marked hypercalciuria, without an increase in intestinal calcium absorption, which suggests that the source of the additional urinary calcium is bone mineral. If renal function is impaired, there is a decrease in the ability to excrete acids, leading to acid retention; yet, the systemic pH, after an initial fall, remains remarkably stable, indicating that the metabolic acids are being buffered — presumably by bone. Patients with a defect in renal acid excretion, distal renal tubular acidosis, have osteopenia () that is substantially corrected by long-term administration of base (). Treatment of postmenopausal women with oral potassium bicarbonate to neutralize endogenous acid production leads to improved calcium retention, reduced bone resorption, and increased bone formation ().
The response of bone in vitro to physiologically relevant acidosis has been studied in some detail. Initially, over the first few hours, there is buffering of the acidic medium pH () through physicochemical dissolution of the bone mineral (), releasing calcium as well as the proton buffer carbonate (), and exchange of bone sodium and potassium for hydrogen ions (). Hours later, cellular mechanisms increase bone resorption and decrease bone formation, both of which help to normalize the systemic pH (). Increased bone resorption further liberates the proton buffers carbonate and phosphate from bone mineral (), and decreased bone formation lessens the amount of acid that is produced during bone mineralization. Acidosis has been shown to increase early immediate response genes in osteoblasts () and to increase osteoblastic prostaglandin E2 secretion (), which leads to an increase in receptor activator of NF-κB ligand expression () and osteoclastic bone resorption.
Thus, bone responds to metabolic acidosis through a coordinated homeostatic response aimed at normalizing systemic pH, at the cost of decreased mineral content; however, until the elegant study by Ludwig et al., the mechanism by which pH was sensed was not clear (). These investigators showed that the ovarian cancer G-protein coupled receptor 1 (OGR1), which was previously described as a receptor for sphingosylphosphorylcholine, acts as a proton-sensing receptor stimulating inositol phosphate (IP) formation. Pertinent to bone, expression profiling by reverse transcriptase-mediated polymerase chain reaction revealed mRNA for OGR1 in MG63 human osteosarcoma cells. The cells responded to physiological acidic pH with increased IP formation. Half-maximal activation was found at pH 7.46, very close to physiologic neutral pH. Using an affinity-purified rabbit polyclonal antibody, OGR1 protein was observed in active osteoblasts, lining cells on the bone surface and matrix-embedded osteocytes in rat bones.
The identification of a proton receptor on bone cells is a remarkable advance, similar to the identification of another ion receptor, that for calcium, approximately a decade ago (). We now know how the increase in hydrogen ion concentration, acidosis, can be sensed by bone cells. The existence of a cell-surface receptor responsive to hydrogen ion concentration helps to support the hypothesis that pH is a primary mediator of bone cell function. As with any significant advance, previously unanswerable questions can now be addressed. Does the proton receptor respond differently to acidosis caused by a decrease in the concentration of bicarbonate (metabolic acidosis), which results in cell-mediated bone resorption, compared with isohydric acidosis caused by an increase in the partial pressure of carbon dioxide (respiratory acidosis), which causes far less bone resorption ()? Are there differences in bone proton receptors in subgroups of patients? Would patients with excess bone proton receptors — if they exist — have more acid-induced bone resorption and respond more favorably to alkali treatment? Would agents that inactivate the receptor preserve bone mineral? Ludwig et al. must be congratulated for identifying a hydrogen ion receptor, and further study should help clarify its role in bone physiology, increase our understanding of proton-mediated bone resorption, and potentially lead to strategies for the preservation of bone mineral, especially in the elderly.
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