title: WNT1-induced Secreted Protein-1 (WISP1), a Novel Regulator of Bone Turnover and Wnt Signaling.
abstract: WISP1/CCN4 (hereafter referred to as WISP1), a member of the CCN family, is found in mineralized tissues and is produced by osteoblasts and their precursors. In this study, Wisp1-deficient (Wisp1(-/-)) mice were generated. Using dual-energy x-ray absorptiometry, we showed that by 3 months, the total bone mineral density of Wisp1(-/-) mice was significantly lower than that of WT mice. Further investigation by micro-computed tomography showed that female Wisp1(-/-) mice had decreased trabecular bone volume/total volume and that both male and female Wisp1(-/-) mice had decreased cortical bone thickness accompanied by diminished biomechanical strength. The molecular basis for decreased bone mass in Wisp1(-/-) mice arises from reduced bone formation likely caused by osteogenic progenitors that differentiate poorly compared with WT cells. Osteoclast precursors from Wisp1(-/-) mice developed more tartrate-resistant acid phosphatase-positive cells in vitro and in transplants, suggesting that WISP1 is also a negative regulator of osteoclast differentiation. When bone turnover (formation and resorption) was induced by ovariectomy, Wisp1(-/-) mice had lower bone mineral density compared WT mice, confirming the potential for multiple roles for WISP1 in controlling bone homeostasis. Wisp1(-/-) bone marrow stromal cells had reduced expression of β-catenin and its target genes, potentially caused by WISP1 inhibition of SOST binding to LRP6. Taken together, our data suggest that the decreased bone mass found in Wisp1(-/-) mice could potentially be caused by an insufficiency in the osteodifferentiation capacity of bone marrow stromal cells arising from diminished Wnt signaling, ultimately leading to altered bone turnover and weaker biomechanically compromised bones.
authors: From the Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, the Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558, Japan.
authors: Azusa
authors: A
authors: Maeda
authors: From the Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, the Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558, Japan.
authors: Mitsuaki
authors: M
authors: Ono
authors: From the Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
authors: Kenn
authors: K
authors: Holmbeck
authors: From the Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
authors: Li
authors: L
authors: Li
authors: From the Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
authors: Tina M
authors: TM
authors: Kilts
authors: From the Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
authors: Vardit
authors: V
authors: Kram
authors: From the Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
authors: Megan L
authors: ML
authors: Noonan
authors: From the Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, the Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama City, Okayama 700-8558, Japan.
authors: Yuya
authors: Y
authors: Yoshioka
authors: Biologic and Materials Sciences and Division of Prosthodontics, University of Michigan, Ann Arbor, Michigan 48109.
authors: Erin M B
authors: EM
authors: McNerny
authors: Biologic and Materials Sciences and Division of Prosthodontics, University of Michigan, Ann Arbor, Michigan 48109.
authors: Margaret A
authors: MA
authors: Tantillo
authors: Biologic and Materials Sciences and Division of Prosthodontics, University of Michigan, Ann Arbor, Michigan 48109.
authors: David H
authors: DH
authors: Kohn
authors: Department of Molecular, Cell and Developmental Biology and the Orthopedic Hospital Department of Orthopedic Surgery, UCLA, Los Angeles, California 90095, and.
authors: Karen M
authors: KM
authors: Lyons
authors: From the Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892.
authors: Pamela G
authors: PG
authors: Robey
authors: From the Craniofacial and Skeletal Diseases Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, myoung@dir.nidcr.nih.gov.
authors: Marian F
authors: MF
authors: Young
mesh_terms: D000483:Alleles; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016723:Bone Remodeling; D001842:Bone and Bones / Q000378:metabolism*; D055511:CCN Intercellular Signaling Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D011995:Recombination, Genetic; D017154:Stromal Cells / Q000166:cytology; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D055114:X-Ray Microtomography
chemical_list: D055511:CCN Intercellular Signaling Proteins; C492067:CCN4 protein, mouse; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins
keywords: WISP1/CCN4; Wnt signaling; aging; bone; bone strength; extracellular matrix protein; osteogenesis; osteopenia; stromal cell