Extracellular pH Regulates Bone Cell Function , ,

Abstract

The skeletons of land vertebrates contain a massive reserve of alkaline mineral (hydroxyapatite), which is ultimately available to buffer metabolic H+ if acid-base balance is not maintained within narrow limits. The negative impact of acidosis on the skeleton has long been known but was thought to result from passive, physicochemical dissolution of bone mineral. This brief, selective review summarizes what is now known of the direct functional responses of bone cells to extracellular pH. We discovered that bone resorption by cultured osteoclasts is stimulated directly by acid. The stimulatory effect is near-maximal at pH 7.0, whereas above pH 7.4, resorption is switched off. In bone organ cultures, H+-stimulated bone mineral release is almost entirely osteoclast-mediated, with a negligible physicochemical component. Acidification is the key requirement for osteoclasts to excavate resorption pits in all species studied to date, and extracellular H+ may thus be regarded as the long-sought osteoclast activation factor. Acid-activated osteoclasts can be stimulated further by agents such as parathyroid hormone, 1,25-dihydroxycholecalciferol, and receptor activator of nuclear factor kappaB ligand. Osteoclasts may respond to pH changes via H+-sensing ion channels such as transient receptor potential vanilloid 1, a nociceptor that is also activated by capsaicin. Acidosis also exerts a powerful, reciprocal inhibitory effect on the mineralization of bone matrix by cultured osteoblasts. This is caused by increased hydroxyapatite solubility at low pH, together with selective inhibition of alkaline phosphatase, which is required for mineralization. Diets or drugs that shift acid-base balance in the alkaline direction may provide useful treatments for bone loss disorders.

Regulated acid–base transport in the collecting duct

“…Deranged acid-base status is associated with higher morbidity and mortality in patients with chronic kidney disease (15). Extracellular pH affects bone density and stability and mild chronic metabolic acidosis has been suspected to contribute to osteopenia and -porosis (10,77). Rickets and osteomalacia are often observed in patients with inborn syndromes of renal tubular acidosis (see below).…”

A neglected requirement for optimizing treatment of age-related osteoporosis: Replenishing the skeleton’s base reservoir with net base-producing diets

“…Two homeostatic mechanisms operate to prevent a serious increase in the acidity and decrease in bicarbonate concentration of body water under conditions of endogenous generation of non-carbonic acids in excess of base: (a) generation of 'new' bicarbonate by the kidney and its delivery to extracellular fluid compartment in conjunction with the excretion of hydrogen ions in the urine as ammonium ions and titratable acid; (b) release of bone mineral base as hydroxyl, phosphate, and carbonate ions and their delivery to the extracellular fluid compartment [8,11,13,[18][19][20]. Thus one of the negative trade-offs for the skeleton's continuing contribution to systemic acid-base homeostasis is continuing loss of the bone's alkaline mineral.…”

“…Together the two mechanisms mitigate the severity of the metabolic acidosis and tend to stabilize it despite continuing endogenous generation non-carbonic acid in excess of base-at the expense of continuing net loss of calcium and its associated alkalinizing anions. In the case of bone's contribution to the homeostasis of acidity and bicarbonate concentration, the mechanism consists in stimulation, by acidity and reduced bicarbonate concentration, of osteoclastic bone resorption and suppression of osteoblastic bone formation, two events that can lead to osteoporosis [10,20].…”

“…The resulting chronic metabolic acidosis elicits osteoclastic bone resorption, which releases bone mineral, including calcium and its accompanying basic anions [8][9][10][11][12][13][14][15]. Most Americans suffer from a low-grade chronic metabolic acidosis owing to the fact that the typical American diet is net acid producing, that is, it produces non-carbonic acid in excess of base (alkali, bicarbonate) [16,17].Two homeostatic mechanisms operate to prevent a serious increase in the acidity and decrease in bicarbonate concentration of body water under conditions of endogenous generation of non-carbonic acids in excess of base: (a) generation of 'new' bicarbonate by the kidney and its delivery to extracellular fluid compartment in conjunction with the excretion of hydrogen ions in the urine as ammonium ions and titratable acid; (b) release of bone mineral base as hydroxyl, phosphate, and carbonate ions and their delivery to the extracellular fluid compartment [8,11,13,[18][19][20]. Thus one of the negative trade-offs for the skeleton's continuing contribution to systemic acid-base homeostasis is continuing loss of the bone's alkaline mineral.…”

“…Together the two mechanisms mitigate the severity of the metabolic acidosis and tend to stabilize it despite continuing endogenous generation non-carbonic acid in excess of base-at the expense of continuing net loss of calcium and its associated alkalinizing anions. In the case of bone's contribution to the homeostasis of acidity and bicarbonate concentration, the mechanism consists in stimulation, by acidity and reduced bicarbonate concentration, of osteoclastic bone resorption and suppression of osteoblastic bone formation, two events that can lead to osteoporosis [10,20].In the treatment of osteoporosis, both of the postmenopausal and age-related types, numerous pharmacological agents have been developed to discourage osteoclastic bone resorption, though secondarily such anti-resorptive agents tend to discourage osteoblastic bone formation. A few agents have been developed to encourage osteoblastic bone formation itself [1,2].…”