Selective Runx2-II deficiency leads to low-turnover osteopenia in adult mice.
Runx2 transcribes Runx2-II and Runx2-I isoforms with distinct N-termini. Deletion of both isoforms results in complete arrest of bone development, whereas selective loss of Runx2-II is sufficient to form a grossly intact skeleton with impaired endochondral bone development. To elucidate the role of Runx2-II in osteoblast function in adult mice, we examined heterozygous Runx2-II (Runx2-II(+/-)) and homozygous Runx2-II (Runx2-II(-/-))-deficient mice, which, respectively, lack one or both copies of Runx2-II but intact Runx2-I expression. Compared to wild-type mice, 6-week-old Runx2-II(+/-) had reduced trabecular bone volume (BV/TV%), cortical thickness (Ct.Th), and bone mineral density (BMD), decreased osteoblastic and osteoclastic markers, lower bone formation rates, impaired osteoblast maturation of BMSCs in vitro, and significant reductions in mechanical properties. Homozygous Runx2-II(-/-) mice had a more severe reduction in BMD, BV/TV%, and Ct.Th, and greater suppression of osteoblastic and osteoclastic markers than Runx2-II(+/-) mice. Non-selective Runx2(+/-) mice, which have an equivalent reduction in Runx2 expression due to the lack one copy of Runx2-I and II, however, had an intermediate reduction in BMD. Thus, selective Runx2-II mutation causes diminished osteoblastic function in an adult mouse leading to low-turnover osteopenia and suggest that Runx2-I and II have distinct functions imparted by their different N-termini.
Xiao
Zhousheng
Z
Internal Medicine/The Kidney Institute, University of Kansas Medical Center, 6018 Wahl Hall East, Kansas City, 66160, USA.
Awad
Hani A
HA
Liu
Shiguang
S
Mahlios
Josh
J
Zhang
Shiqin
S
Guilak
Farshid
F
Mayo
Matthew S
MS
Quarles
Leigh Darryl
LD
D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005269:Femur / Q000000981:diagnostic imaging / Q000254:growth & development; D020869:Gene Expression Profiling; D005838:Genotype; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013131:Spine / Q000000981:diagnostic imaging / Q000254:growth & development; D014057:Tomography, X-Ray Computed; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; C493716:Runx2 protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors