TY - JOUR
T1 - Preservation of type H vessels and osteoblasts by enhanced preosteoclast platelet-derived growth factor type BB attenuates glucocorticoid-induced osteoporosis in growing mice
AU - Yang, Ping
AU - Lv, Shan
AU - Wang, Yan
AU - Peng, Yi
AU - Ye, Zixing
AU - Xia, Zhuying
AU - Ding, Guoxian
AU - Cao, Xu
AU - Crane, Janet L.
N1 - Funding Information:
Grant support was provided by NIH/NIAMS K08-AR064833 (J.C), and R01-AR063943 (X.C), and the Pediatric Endocrine Society Clinical Scholar Award (JC). Confocal Microscopy funding by NIH OD/ORIP S10 OD016374. Authors' roles: Study design: PY, SL, YW and JC. Study conduct: PY, SL, YW, YP, and JC. Data collection: PY, YW, ZY, SL, ZX, YP, JC. Data analysis: PY, YW, SL, YP, and JC. Data interpretation: PY, YW, SL, and JC. Drafting manuscript: PY, YW, SL, and JC. Revising manuscript content: PY, YW, SL, YP, XC and JC. Approving final version of manuscript: PY, YW, ZY, SL, ZX, YP, GD, XC, and JC. PY, YW, SL, YP, and JC take responsibility for the integrity of the data analysis.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/9
Y1 - 2018/9
N2 - Survival of chronic diseases in childhood is often achieved utilizing glucocorticoids, but comes with significant side effects, including glucocorticoid-induced osteoporosis (GIO). Knowledge of the mechanism of GIO is limited to the adult skeleton. We explored the effect of genetic loss and inhibition of cathepsin K (Ctsk) as a potential treatment target in a young GIO mouse model as genetic loss of cathepsin K results in a mild form of osteopetrosis secondary to impaired osteoclast bone resorption with maintenance of bone formation. We first characterized the temporal osteoclast and osteoblast progenitor populations in Ctsk−/− and wild type (WT) mice in the primary and secondary spongiosa, as sites representative of trabecular bone modeling and remodeling, respectively. In the primary spongiosa, Ctsk−/− mice had decreased numbers of osteoclasts at young ages (2 and 4 weeks) and increased osteoblast lineage cells at later age (8 weeks) relative to WT littermates. In the secondary spongiosa, Ctsk−/− mice had greater numbers of osteoclasts and osteoblast lineage cells relative to WT littermates. We next developed a young GIO mouse model with prednisolone 10 mg/m2/day injected intraperitoneally daily from 2 through 6 weeks of age. Overall, WT-prednisolone mice had lower bone volume per tissue volume, whereas Ctsk−/−-prednisolone mice maintained a similar bone volume relative to Ctsk−/−-vehicle controls. WT-prednisolone mice exhibited a decreased number of osteoclasts, tartrate-resistant acid phosphatase and platelet-derived growth factor type BB (PDGF-BB) co-positive cells, type H endothelial cells, and osteoblasts relative to WT-vehicle mice in both the primary and secondary spongiosa. Interestingly, Ctsk−/−-prednisolone mice demonstrated a paradoxical response with increased numbers of all parameters in primary spongiosa and no change in secondary spongiosa. Finally, treatment with a cathepsin K inhibitor prevented WT-prednisolone decline in osteoclasts, osteoblasts, type H vessels, and bone volume. These data demonstrate that cells in the primary and secondary spongiosa respond differently to glucocorticoids and genetic manipulation. Inhibition of osteoclast resorption that preserves osteoclast coupling factors, such as through inhibition of cathepsin K, may be a potential preventive treatment strategy against GIO in the growing skeleton.
AB - Survival of chronic diseases in childhood is often achieved utilizing glucocorticoids, but comes with significant side effects, including glucocorticoid-induced osteoporosis (GIO). Knowledge of the mechanism of GIO is limited to the adult skeleton. We explored the effect of genetic loss and inhibition of cathepsin K (Ctsk) as a potential treatment target in a young GIO mouse model as genetic loss of cathepsin K results in a mild form of osteopetrosis secondary to impaired osteoclast bone resorption with maintenance of bone formation. We first characterized the temporal osteoclast and osteoblast progenitor populations in Ctsk−/− and wild type (WT) mice in the primary and secondary spongiosa, as sites representative of trabecular bone modeling and remodeling, respectively. In the primary spongiosa, Ctsk−/− mice had decreased numbers of osteoclasts at young ages (2 and 4 weeks) and increased osteoblast lineage cells at later age (8 weeks) relative to WT littermates. In the secondary spongiosa, Ctsk−/− mice had greater numbers of osteoclasts and osteoblast lineage cells relative to WT littermates. We next developed a young GIO mouse model with prednisolone 10 mg/m2/day injected intraperitoneally daily from 2 through 6 weeks of age. Overall, WT-prednisolone mice had lower bone volume per tissue volume, whereas Ctsk−/−-prednisolone mice maintained a similar bone volume relative to Ctsk−/−-vehicle controls. WT-prednisolone mice exhibited a decreased number of osteoclasts, tartrate-resistant acid phosphatase and platelet-derived growth factor type BB (PDGF-BB) co-positive cells, type H endothelial cells, and osteoblasts relative to WT-vehicle mice in both the primary and secondary spongiosa. Interestingly, Ctsk−/−-prednisolone mice demonstrated a paradoxical response with increased numbers of all parameters in primary spongiosa and no change in secondary spongiosa. Finally, treatment with a cathepsin K inhibitor prevented WT-prednisolone decline in osteoclasts, osteoblasts, type H vessels, and bone volume. These data demonstrate that cells in the primary and secondary spongiosa respond differently to glucocorticoids and genetic manipulation. Inhibition of osteoclast resorption that preserves osteoclast coupling factors, such as through inhibition of cathepsin K, may be a potential preventive treatment strategy against GIO in the growing skeleton.
KW - Bone vasculature
KW - Glucocorticoid induced osteoporosis
KW - Mice
KW - Postnatal growth
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U2 - 10.1016/j.bone.2018.05.025
DO - 10.1016/j.bone.2018.05.025
M3 - Article
C2 - 29800693
AN - SCOPUS:85047757603
SN - 8756-3282
VL - 114
SP - 1
EP - 13
JO - Bone
JF - Bone
ER -