Zoledronic acid improves bone histomorphometry in a murine model of Rett syndrome.
Rett syndrome (RTT) is a neurodevelopmental disorder predominately affecting young females, caused by deficiency of the global transcriptional protein methyl CpG binding protein 2 (MeCP2). Osteoblasts express MeCP2 and girls with RTT experience early onset osteoporosis, decreased bone mass and an increased fracture risk. There is no defined treatment for osteoporosis associated with RTT. The present study evaluated the effects of zoledronic acid (ZA), a third generation nitrogen-containing bisphosphonate with primarily anti-osteoclastic activity, in a mouse model of MeCP2 deficiency. Mice received weekly injections of 20μg/kg ZA for six weeks. Due to the shortened lifespan of hemizygous male (Mecp2-null) mice, treatment began at 3weeks of age for this group and corresponding wildtype (WT) male mice. Treatment for heterozygous (HET) and WT female mice began at 8weeks of age. Micro-computed tomography (micro-CT) and dynamic analyses of bone turnover were performed. ZA treatment led to significant increases in bone volume fraction, number, connectivity density and apparent density of trabecular bone in all genotypes of mice. In contrast, cortical bone generally was unaffected by ZA injections. Parameters of bone turnover, including mineral apposition rate, labeled bone surface and bone formation rate decreased after treatment with ZA. Mecp2-null mice had reduced labeled bone surface and bone formation rate compared to WT male mice. The results indicate that ZA treatment significantly improved trabecular bone mass in a murine model of RTT with little effect on cortical bone.
Hugo W. Moser Research Institute at Kennedy Krieger, Inc., 707 North Broadway, Baltimore, MD 21205, USA.
Jay R
JR
Shapiro
Hospital for Special Surgery, Mineralized Tissue Laboratory, 535 E 70th Street, New York, NY 10021, USA. Electronic address: BoskeyA@HSS.EDU.
Adele L
AL
Boskey
Hospital for Special Surgery, Mineralized Tissue Laboratory, 535 E 70th Street, New York, NY 10021, USA. Electronic address: DotyS@HSS.EDU.
Stephen B
SB
Doty
Hospital for Special Surgery, Mineralized Tissue Laboratory, 535 E 70th Street, New York, NY 10021, USA. Electronic address: LukashovaL@HSS.EDU.
Lyudmila
L
Lukashova
Hugo W. Moser Research Institute at Kennedy Krieger, Inc., 707 North Broadway, Baltimore, MD 21205, USA. Electronic address: blue@kennedykrieger.org.
Mary E
ME
Blue
D000818:Animals; D000071556:Cancellous Bone / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071538:Cortical Bone / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004164:Diphosphonates / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015518:Rett Syndrome / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D000077211:Zoledronic Acid
Bone histomorphometry; Bone turnover; MeCP2; Micro-CT; Mouse model; Rett syndrome; Zoledronic acid