Secreted frizzled-related protein 1 modulates glucocorticoid attenuation of osteogenic activities and bone mass.
Prolonged glucocorticoid treatment is known to cause osteoporosis or aseptic necrosis. Secreted frizzled-related proteins 1 (SFRP1) and low-density lipoprotein-related protein 5 (LRP5), a Wnt protein antagonist and a coreceptor, have been found to regulate skeletogenesis. Whereas recent studies have reported that excess glucocorticoid promotes bone loss, the biological role of SFRP1 and LRP5 in regulating glucocorticoid attenuation of bone formation is not fully understood. We showed that a supraphysiological level of glucocorticoid enhanced SFRP1 but not LRP5 expression of primary mesenchymal cell cultures in vitro and osteoblasts at metaphyseal trabecular endosteum and chondrocytes at calcified cartilage in vivo. Glucocorticoid augmentation of SFRP1 expression was transcriptionally mediated. The inhibitory action of glucocorticoid on osteogenic differentiation appeared to be regulated by SFRP1 mediation of beta-catenin destabilization because knocking down SFRP1 by RNA interference abrogated the supraphysiological level of glucocorticoid attenuation of osteogenesis. Recombinant human SFRP1 reduced the promoting effect of physiological level of glucocorticoid on cytosolic beta-catenin accumulation, runt-related transcription factor-2 activation, and osteogenic activities. Glucocorticoid and recombinant human SFRP1 significantly increased osteochondral cell apoptosis associated with reduced mineral density, biomechanical properties, trabecular bone volume, and midshaft cortical bone areas in rat femurs. These findings suggest that SFRP1 modulates glucocorticoid-induced bone loss. Regulation of Wnt/SFRP signal transduction can be used in the future as an alternative strategy for the prevention of glucocorticoid-induced osteoporosis.
Wang
Feng-Sheng
FS
Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Niao Sung, Kaohsiung 833, Taiwan.
Lin
Chun-Liang
CL
Chen
Yeung-Jen
YJ
Wang
Ching-Jen
CJ
Yang
Kuender D
KD
Huang
Yu-Ting
YT
Sun
Yi-Chih
YC
Huang
Hui-Chen
HC
D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects* / Q000502:physiology*; D001842:Bone and Bones / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D002455:Cell Division; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000378:metabolism; D005269:Femur; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008648:Mesoderm / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000032:analysis; D010012:Osteogenesis / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects; D051176:beta Catenin; D000094742:Secreted Frizzled-Related Proteins
D003598:Cytoskeletal Proteins; D005938:Glucocorticoids; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011973:Receptors, LDL; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; C555482:LRP5 protein, human; C555484:Lrp5 protein, rat; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C500646:Sfrp1 protein, rat