Palle Christophersen

Acidification of the Osteoclastic Resorption Compartment Provides Insight into the Coupling of Bone Formation to Bone Resorption

Patients with defective osteoclastic acidification have increased numbers of osteoclasts, with decreased resorption, but bone formation that remains unchanged. We demonstrate that osteoclast survival is increased when acidification is impaired, and that impairment of acidification results in inhibition of bone resorption without inhibition of bone formation. We investigated the role of acidification in human osteoclastic resorption and life span in vitro using inhibitors of chloride channels (NS5818/NS3696), the proton pump (bafilomycin) and cathepsin K. We found that bafilomycin and NS5818 dose dependently inhibited acidification of the osteoclastic resorption compartment and bone resorption. Inhibition of bone resorption by inhibition of acidification, but not cathepsin K inhibition, augmented osteoclast survival, which resulted in a 150 to 300% increase in osteoclasts compared to controls. We investigated the effect of inhibition of osteoclastic acidification in vivo by using the rat ovariectomy model with twice daily oral dosing of NS3696 at 50 mg/kg for 6 weeks. We observed a 60% decrease in resorption (DPYR), increased tartrate-resistant acid phosphatase levels, and no effect on bone formation evaluated by osteocalcin. We speculate that attenuated acidification inhibits dissolution of the inorganic phase of bone and results in an increased number of nonresorbing osteoclasts that are responsible for the coupling to normal bone formation. Thus, we suggest that acidification is essential for normal bone remodeling and that attenuated acidification leads to uncoupling with decreased bone resorption and unaffected bone formation.

The Chloride Channel Inhibitor NS3736 Prevents Bone Resorption in Ovariectomized Rats Without Changing Bone Formation

Chloride channel activity is essential for osteoclast function. Consequently, inhibition of the osteoclastic chloride channel should prevent bone resorption. Accordingly, we tested a chloride channel inhibitor on bone turnover and found that it inhibits bone resorption without affecting bone formation. This study indicates that chloride channel inhibitors are highly promising for treatment of osteoporosis.

Recent Developments in the Pharmacology of Epithelial Ca2+-Activated K+ Channels

Calcium (Ca2+)-activated potassium (K+) channels (KCa) in epithelia serve important functions in fluid and salt secretion and may be attractive targets for drug development for epithelial disorders, such as cystic fibrosis, diarrhoea, COPD, polycystic kidney disease, and glaucoma. Two very different types of KCa channels are generally found in epithelia: the big conductance, Ca2+-activated K+ channel (BK, KCa1.1), and the intermediate conductance, Ca2+-activated K+ channel (IK, KCa3.1). These channels are differentially expressed in various cells and tissues and serve different physiological and potentially also pathophysiological functions in epithelia.