title: Lactating Ctcgrp nulls lose twice the normal bone mineral content due to fewer osteoblasts and more osteoclasts, whereas bone mass is fully restored after weaning in association with up-regulation of Wnt signaling and other novel genes.
abstract: The maternal skeleton resorbs during lactation to provide calcium to milk and the lost mineral content is restored after weaning. The changes are particularly marked in Ctcgrp null mice, which lose 50% of spine mineral content during lactation but restore it fully. The known calciotropic hormones are not required for skeletal recovery to occur; therefore, unknown factors that stimulate bone formation may be responsible. We hypothesized that the genes responsible for regulating postweaning bone formation are differentially regulated in bone or marrow, and this regulation may be more marked in Ctcgrp null mice. We confirmed that Ctcgrp null mice had twice as many osteoclasts and 30-40% fewer osteoblasts as compared with wild-type mice during lactation but no deficit in osteoblast numbers after weaning. Genome-wide microarray analyses on tibial RNA showed differential expression of 729 genes in wild-type mice at day 7 after weaning vs prepregnancy, whereas the same comparison in Ctcgrp null mice revealed only 283 genes. Down-regulation of Wnt family inhibitors, Sost and Dkk1, and inhibition of Mef2c, a sclerostin stimulator, were observed. Ctsk, a gene expressed during osteoclast differentiation, and Igfbp2, which stimulates bone resorption, were inhibited. Differential regulation of genes involved in energy use was compatible with a net increase in bone formation. The most marked changes occurred in genes not previously associated with bone metabolism. In conclusion, the postlactation skeleton shows dynamic activity with more than 700 genes differentially expressed. Some of these genes are likely to promote bone formation during postweaning by stimulating the proliferation and activity of osteoblasts, inhibiting osteoclasts, and increasing energy use.
authors: Faculty of Medicine—Endocrinology, Memorial University of Newfoundland, St John’s, Newfoundland, Canada A1B 3V6.
authors: Jillian N
authors: JN
authors: Collins
authors: Beth J
authors: BJ
authors: Kirby
authors: Janine P
authors: JP
authors: Woodrow
authors: Robert F
authors: RF
authors: Gagel
authors: Clifford J
authors: CJ
authors: Rosen
authors: Natalie A
authors: NA
authors: Sims
authors: Christopher S
authors: CS
authors: Kovacs
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics* / Q000502:physiology; D001846:Bone Development / Q000235:genetics; D001862:Bone Resorption / Q000235:genetics; D001842:Bone and Bones / Q000166:cytology / Q000502:physiology; D002113:Calcification, Physiologic / Q000235:genetics* / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling; D007774:Lactation / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000502:physiology*; D010010:Osteoclasts / Q000502:physiology*; D013977:Tibia / Q000378:metabolism; D015854:Up-Regulation; D014886:Weaning; D060449:Wnt Signaling Pathway / Q000235:genetics* / Q000502:physiology
chemical_list: D002118:Calcium