Secreted frizzled related protein 1 is a target to improve fracture healing.
Genetic studies have identified a high bone mass of phenotype in both human and mouse when canonical Wnt signaling is increased. Secreted frizzled related protein 1 (sFRP1) is one of several Wnt antagonists and among the loss-of-function mouse models in which 32-week-old mice exhibit a high bone mass phenotype. Here we show that impact fracture healing is enhanced in this mouse model of increased Wnt signaling at a physiologic level in young (8 weeks) sFRP1(-/-) mice which do not yet exhibit significant increases in BMD. In vivo deletion of sFRP1 function improves fracture repair by promoting early bone union without adverse effects on the quality of bone tissue reflected by increased mechanical strength. We observe a dramatic reduction of the cartilage callous, increased intramembranous bone formation with bone bridging by 14 days, and early bone remodeling during the 28-day fracture repair process in the sFRP1(-/-) mice. Our molecular analyses of gene markers indicate that the effect of sFRP1 loss-of-function during fracture repair is to accelerate bone healing after formation of the initial hematoma by directing mesenchymal stem cells into the osteoblast lineage via the canonical pathway. Further evidence to support this conclusion is the observation of maximal sFRP1 levels in the cartilaginous callus of a WT mouse. Hence sFRP1(-/-) mouse progenitor cells are shifted directly into the osteoblast lineage. Thus, developing an antagonist to specifically inhibit sFRP1 represents a safe target for stimulating fracture repair and bone formation in metabolic bone disorders, osteoporosis and aging.
Gaur
Tripti
T
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Wixted
John J
JJ
Hussain
Sadiq
S
O'Connell
Shannon L
SL
Morgan
Elise F
EF
Ayers
David C
DC
Komm
Barry S
BS
Bodine
Peter V
PV
Stein
Gary S
GS
Lian
Jane B
JB
D000818:Animals; D016723:Bone Remodeling / Q000235:genetics; D002146:Bony Callus / Q000378:metabolism / Q000503:physiopathology; D002356:Cartilage / Q000378:metabolism / Q000503:physiopathology; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D004195:Disease Models, Animal; D017102:Fracture Healing / Q000235:genetics; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D011859:Radiography; D015398:Signal Transduction; D013977:Tibia / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D013978:Tibial Fractures / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D051153:Wnt Proteins / Q000378:metabolism; D000094742:Secreted Frizzled-Related Proteins
D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051153:Wnt Proteins; C485539:Sfrp1 protein, mouse; D000094742:Secreted Frizzled-Related Proteins