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Background: Osteopetrosis, a genetic disease characterised by osteoclast failure, is classified into three forms: infantile malignant autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IRO), and autosomal dominant osteopetrosis (ADO). Methods: We studied 49 patients, 21 with ARO, one with IRO, and 27 with type II ADO (ADO II). Results: Most ARO patients bore known or novel (one case) ATP6i (TCIRG1) gene mutations. Six ADO II patients had no mutations in ClCN7, the only so far recognised gene implicated, suggesting involvement of yet unknown genes. Identical ClCN7 mutations produced differing phenotypes with variable degrees of severity. In ADO II, serum tartrate resistant acid phosphatase was always elevated. Bone alkaline phosphatase (BALP) was generally low, but osteocalcin was high, suggesting perturbed osteoblast differentiation or function. In contrast, BALP was high in ARO patients. Elevated osteoclast surface/bone surface was noted in biopsies from most ARO patients. Cases with high osteoclasts also showed increased osteoblast surface/bone surface. ARO osteoclasts were morphologically normal, with unaltered formation rates, intracellular pH handling, and response to acidification. Their resorption activity was greatly reduced, but not abolished. In control osteoclasts, all resorption activity was abolished by combined inhibition of proton pumping and sodium/proton antiport. Conclusions: These findings provide a rationale for novel therapies targeting pH handling mechanisms in osteoclasts and their microenvironment.

Cidofovir may be a potentially effective therapy for BKV-HC, but evidence supporting its use requires randomized controlled trials.

Autosomal-recessive osteopetrosis is a severe genetic disease caused by osteoclast failure. Approximately 50% of the patients harbor mutations of the ATP6i gene, encoding for the osteoclast-specific a3 subunit of V-ATPase. We found inactivating ATP6i mutations in four patients, and three of these were novel. Patients shared macrocephaly, growth retardation and optic nerve alteration, osteosclerotic and endobone patterns, and high alkaline phosphatase and parathyroid hormone levels. Bone biopsies revealed primary spongiosa lined with active osteoblasts and high numbers of tartrate-resistant acid phosphatase (TRAP)-positive, a3 subunit-negative, morphologically unremarkable osteoclasts, some of which located in shallow Howship lacunae. Scarce hematopoietic cells and abundant fibrous tissue containing TRAP-positive putative osteoclast precursors were noted. In vitro osteoclasts were a3-negative, morphologically normal, with prominent clear zones and actin rings, and TRAP activity more elevated than in control patients. The osteoclast vacuolar-type translocating ATPase (VATPase) is central to the mechanism of bone resorption. It is located in the ruffled border membrane where it releases protons underneath the resorbing lacuna, acidifying this microenvironment and permitting solubilization of the hydroxyapatite crystals.1-3 This event requires continuous release of protons because of the high-buffering capacity of phosphates, and 8 mol of H ϩ are required to solubilize 1 mol of hydroxyapatite.4 Therefore, efficient activity of the V-ATPase is mandatory for bone matrix demineralization.The V-ATPase shares similarity with the F 0 -F 1 ATPsynthase complex present in mitochondria, chloroplasts, and bacteria.5-8 It consists of a V 0 transmembrane proton channel and a V 1 ATP hydrolytic domain. The structure of the V 1 complex is well defined. It is a 570-kd peripheral protein composed of eight subunits (A to H), with three copies of the A and B subunits and single copies of the remaining subunits. The V 0 transmembrane domain contains five subunits (a, d, c, cЈ, and cЉ), with six copies of c and cЈ, and single copies of the others. c, cЈ, and cЉ subunits span the membrane and contribute to the organization of the proton channel. The a subunit is found in three isoforms, a1, a2, and a3, with the a3 being the one that is osteoclast-specific. 5,9 -11 Transcription of this subunit increases in resorption-competent osteoclasts and the protein is transferred to the ruffled border membrane during the process of cell polarization. 12,13The a subunit is a transmembrane glycoprotein possessing a large N-terminal hydrophilic domain and a C-terminal hydrophobic domain, containing multiple putative transmembrane helices. It has several buried charged residues that appear to be in a position to influence proton translocation. It also emerges to possess the binding site for the V-ATPase inhibitor bafilomycin.

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