PTH receptor 1 expression in osteocytes is indispensable for the anabolic effect of mechanical loading in mice

TU XIAOLIN; PELLEGRINI GG; GALLI C; BENSON J; CONDON K; BIVI N; PLOTKIN L; ROBLING A; BELLIDO T

Congreso; American Association for Bone and MIneral Reseach; 2011

Osteocytes play an essential role in skeletal homeostasis by integrating the responses of bone to mechanical and hormonal stimuli. Both mechanical loading and activation of the PTH receptor 1 (PTHR1) in osteocytes promote new bone formation by downregulating the expression of sclerostin, the inhibitor of bone formation secreted by osteocytes, and thereby activating the Wnt pathway. To explore a potential crosstalk between PTHR1 signaling and mechanotransduction, we examined the osteogenic response to loading of mice lacking the PTHR1 specifically in osteocytes (cKO). Mice were generated by crossing PTHR1flox/flox mice, in which the E1 exon of the PTHR1 is flanked by loxP sites, with DMP1-8kb-Cre mice, which express Cre recombinase in osteocytes but not in osteoblasts. PTHR1 mRNA was reduced in all bones examined, in particular by 73% in long bones of cKO mice compared to control PTHR1flox/flox littermates. Female, 4 month-old cKO mice exhibited no significant changes in ulnae geometry or in material density. However, ex vivo loading induced 20% higher strains in cKO mice (1541.7µå/N) compared to controls (1229.1µå/N), indicating less resistance of cKO bones to mechanical force. Right ulnae from control and cKO mice were loaded at equal strains of low, medium, and high magnitude during 1min/day for 3 consecutive days and sacrificed 14 days later; left ulnae were non-loaded controls. Dynamic histomorphometric analysis revealed that basal periosteal bone formation rate (BFR) was similar in control and cKO mice. Loading caused a strain-dependent increase in BFR in controls (0.13±0.06; 0.18±0.13; and 0.38±0.15 um3/um2/d), resulting from an increase in both mineralizing surface covered by osteoblasts (MS/BS) as well as activity of individual osteoblasts (MAR). In contrast, loading-induced BFR was dramatically reduced in cKO mice by 23%, 44%, and 71% (0.10±0.05, 0.10±0.05, and 0.11±0.08 um3/um2/day) with minimal but significant changes induced only by medium and high strains. This effect resulted mainly from the lack of stimulation of MAR by loading at any strain magnitude. Loading-induced MS/BS was also reduced in the cKO mice, with significant increases induced only by medium and high strains. We conclude that signaling downstream of the PTHR1 in osteocytes is required for the osteogenic response induced by mechanical force.   Characters with spaces: 2362 (2500 max);   Categories: B. Osteocytes; or                    F. Calciotropic and Phosphotropic Hormones and Mineral Metabolism Poster cluster:   B. Osteocytes: Regulation of Bone Formation; or                      F.    Calciotropic and Phosphotropic Hormones: Parathyroid and Parathyroid Hormone-Related Peptide Key words:  Osteocytes, PTHR1, PTHrP, Sost/Sclerostin, Mechanical Loading, Bone Formation, Wnt Signaling