Mechanism of acid-induced bone resorption

Abstract

Purpose of reviewThis review presents our current understanding of the way metabolic acidosis induces calcium efflux from bone, and in the process, buffers additional systemic hydrogen ions associated with acidosis. Recent findingsAcid-induced changes in bone mineral are consistent with a role for bone as a proton buffer. In response to metabolic acidosis in an in-vitro bone organ culture system, we observed a fall in mineral sodium, potassium, carbonate and phosphate, which each buffer protons and in vivo should increase systemic pH towards the physiologic normal. Initially, metabolic acidosis stimulates physicochemical mineral dissolution and subsequently cell-mediated bone resorption. Acidosis suppresses the activity of bone-resorbing cells, osteoblasts, decreasing gene expression of specific matrix proteins and alkaline phosphatase activity. There is concomitant acid stimulation of prostaglandin production by osteoblasts, which acting in a paracrine manner increases synthesis of the osteoblastic receptor activator of nuclear factor kappa B ligand (RANKL). The acid induction of RANKL then stimulates osteoclastic activity and recruitment of new osteoclasts to promote bone resorption and buffering of the proton load. Both the regulation of RANKL and acid-induced calcium efflux from bone are mediated by prostaglandins. Summary Metabolic acidosis, which occurs during renal failure, renal insufficiency or renal tubular acidosis, results in decreased systemic pH and is associated with an increase in urine calcium excretion. The apparent protective function of bone to help maintain systemic pH, which has a clear survival advantage for mammals, will come partly at the expense of its mineral stores. Abbreviations GAPDH glyceraldehyde-3-phosphate dehydrogenase HCO 3 7 bicarbonate ion MGP matrix gla protein PGHS prostaglandin G/H synthase PTH parathyroid hormone RANK receptor activator of nuclear factor kappa B RANKL receptor activator of nuclear factor kappa B ligand TGF-b transforming growth factor beta

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

“…Acidosis has been reported to directly inhibit osteoblast activity, resulting in a reduction in the bone resorbing of minerals and Ca 2+ . 3,70,71 Acidosis may also activate osteoclast activity to increase Ca 2+ release in vitro. 71 Ca 2+ release and mineral dissolution from bone may help systemically buffer protons and restore normal physiological pH.…”

“…Systemic acidosis can occur from respiratory, renal, and metabolic diseases and septic shock. [1][2][3][4]9 Additionally, local acidosis is characterized in ischemic tissues, tumors, and chronically inflamed conditions such as in asthma and arthritis caused by deregulated metabolism and hypoxia. [10][11][12][13][14][15] Acidosis is a stress for the cell.…”

“…Some regulatory mechanisms to control systemic pH are respiration, renal excretion, bone buffering, and metabolism. [1][2][3][4] The respiratory system can buffer the blood by excreting carbonic acid as CO 2 while the kidney responds to decreased circulatory pH by excreting protons and electrolytes to stabilize the 100 Sanderlin et al physiological pH. Bone buffering helps maintain systemic pH by Ca 2+ reabsorption and mineral dissolution.…”

American Society of Nephrology Quiz and Questionnaire 2014

“…The history of nephrolithiasis is also typical of distal RTA (44). In the presence of metabolic acidosis, the bone serves as an important buffer and exchanges H+ ions for sodium, calcium, and potassium that are complexed to carbonates and phosphates (44). Over time, this leads to increased bone resorption with increased calcium and phosphate release and hypercalciuria with hyperphosphaturia.…”

Osteoclast Genetic Diseases

“…However, the use of glucocorticoids leads to a reduction of bone mass due to a direct negative effect on osteoblast activity and to inhibition of osteoclasts, that result in the interruption of the bone remodeling cycle (Dovio et al, 2004). Furthermore, osteoclasts are very sensitive to pH levels as it is known that systemic acidosis has detrimental effects on the skeleton and local acidosis is associated with bone destruction (Arnett, 2003;Krieger et al, 2004;Muzylak et al, 2007). It has been shown that the Ovarian cancer G-protein-coupled Receptor 1 (OGR1 or GPR68), a proton sensing receptor, is essential for osteoclast formation inducing RANKLdependent osteoclastogenesis and activating NFATc1 (Iwai et al, 2007).…”