PTHrP-Derived Peptides Restore Bone Mass and Strength in Diabetic Mice: Additive Effect of Mechanical Loading.
There is an unmet need to understand the mechanisms underlying skeletal deterioration in diabetes mellitus (DM) and to develop therapeutic approaches to treat bone fragility in diabetic patients. We demonstrate herein that mice with type 1 DM induced by streptozotocin exhibited low bone mass, inferior mechanical and material properties, increased bone resorption, decreased bone formation, increased apoptosis of osteocytes, and increased expression of the osteocyte-derived bone formation inhibitor Sost/sclerostin. Further, short treatment of diabetic mice with parathyroid hormone related protein (PTHrP)-derived peptides corrected these changes to levels undistinguishable from non-diabetic mice. In addition, diabetic mice exhibited reduced bone formation in response to mechanical stimulation, which was corrected by treatment with the PTHrP peptides, and higher prevalence of apoptotic osteocytes, which was reduced by loading or by the PTHrP peptides alone and reversed by a combination of loading and PTHrP peptide treatment. In vitro experiments demonstrated that the PTHrP peptides or mechanical stimulation by fluid flow activated the survival kinases ERKs and induced nuclear translocation of the canonical Wnt signaling mediator β-catenin, and prevented the increase in osteocytic cell apoptosis induced by high glucose. Thus, PTHrP-derived peptides cross-talk with mechanical signaling pathways to reverse skeletal deterioration induced by DM in mice. These findings suggest a crucial role of osteocytes in the harmful effects of diabetes on bone and raise the possibility of targeting these cells as a novel approach to treat skeletal deterioration in diabetes. Moreover, our study suggests the potential therapeutic efficacy of combined pharmacological and mechanical stimuli to promote bone accrual and maintenance in diabetic subjects. © 2016 American Society for Bone and Mineral Research.
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
Marta
M
Maycas
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
Kevin A
KA
McAndrews
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Amy Y
AY
Sato
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Gretel G
GG
Pellegrini
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Drew M
DM
Brown
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Matthew R
MR
Allen
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.
Lilian I
LI
Plotkin
Instituto de Medicina Molecular Aplicada-Universidad San Pablo CEU, Madrid, Spain.
Arancha R
AR
Gortazar
Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Madrid, Spain.
Pedro
P
Esbrit
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.|Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA.|Department of Medicine, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, USA.
Teresita
T
Bellido
D048868:Adaptor Proteins, Signal Transducing; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000235:genetics / Q000473:pathology; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000473:pathology* / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D044162:Parathyroid Hormone-Related Protein / Q000494:pharmacology*; D016474:Weight-Bearing
D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D044162:Parathyroid Hormone-Related Protein; C486030:Sost protein, mouse
DIABETES; OSTEOCYTE APOPTOSIS; OSTEOCYTES; PTHrP; SOST/SCLEROSTIN