Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment.
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.
Del Fattore
A
A
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
Peruzzi
B
B
Rucci
N
N
Recchia
I
I
Cappariello
A
A
Longo
M
M
Fortunati
D
D
Ballanti
P
P
Iacobini
M
M
Luciani
M
M
Devito
R
R
Pinto
R
R
Caniglia
M
M
Lanino
E
E
Messina
C
C
Cesaro
S
S
Letizia
C
C
Bianchini
G
G
Fryssira
H
H
Grabowski
P
P
Shaw
N
N
Bishop
N
N
Hughes
D
D
Kapur
R P
RP
Datta
H K
HK
Taranta
A
A
Fornari
R
R
Migliaccio
S
S
Teti
A
A
D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000097:blood; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology; D010022:Osteopetrosis / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D010744:Phosphoric Monoester Hydrolases / Q000097:blood; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics*
C097540:CLCN7 protein, human; D018118:Chloride Channels; D017923:Sodium-Hydrogen Exchangers; C472421:TCIRG1 protein, human; D015675:Osteocalcin; D000469:Alkaline Phosphatase; D010744:Phosphoric Monoester Hydrolases; D025262:Vacuolar Proton-Translocating ATPases