Inhibition of CaMKK2 Enhances Fracture Healing by Stimulating Indian Hedgehog Signaling and Accelerating Endochondral Ossification.

Autor: Williams JN; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Kambrath AV; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Patel RB; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Kang KS; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Mével E; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Li Y; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Cheng YH; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA., Pucylowski AJ; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Hassert MA; Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO, USA., Voor MJ; Department of Orthopaedic Surgery, University of Louisville School of Medicine, Louisville, KY, USA.; Department of Bioengineering, University of Louisville Speed School of Engineering, Louisville, KY, USA., Kacena MA; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA., Thompson WR; Department of Physical Therapy, School of Health and Rehabilitation Sciences, Indiana University, Indianapolis, IN, USA., Warden SJ; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Physical Therapy, School of Health and Rehabilitation Sciences, Indiana University, Indianapolis, IN, USA., Burr DB; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Allen MR; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, USA., Robling AG; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA., Sankar U; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
Jazyk: angličtina
Zdroj: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2018 May; Vol. 33 (5), pp. 930-944. Date of Electronic Publication: 2018 Feb 05.
DOI: 10.1002/jbmr.3379
Abstrakt: Approximately 10% of all bone fractures do not heal, resulting in patient morbidity and healthcare costs. However, no pharmacological treatments are currently available to promote efficient bone healing. Inhibition of Ca 2+ /calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) reverses age-associated loss of trabecular and cortical bone volume and strength in mice. In the current study, we investigated the role of CaMKK2 in bone fracture healing and show that its pharmacological inhibition using STO-609 accelerates early cellular and molecular events associated with endochondral ossification, resulting in a more rapid and efficient healing of the fracture. Within 7 days postfracture, treatment with STO-609 resulted in enhanced Indian hedgehog signaling, paired-related homeobox (PRX1)-positive mesenchymal stem cell (MSC) recruitment, and chondrocyte differentiation and hypertrophy, along with elevated expression of osterix, vascular endothelial growth factor, and type 1 collagen at the fracture callus. Early deposition of primary bone by osteoblasts resulted in STO-609-treated mice possessing significantly higher callus bone volume by 14 days following fracture. Subsequent rapid maturation of the bone matrix bestowed fractured bones in STO-609-treated animals with significantly higher torsional strength and stiffness by 28 days postinjury, indicating accelerated healing of the fracture. Previous studies indicate that fixed and closed femoral fractures in the mice take 35 days to fully heal without treatment. Therefore, our data suggest that STO-609 potentiates a 20% acceleration of the bone healing process. Moreover, inhibiting CaMKK2 also imparted higher mechanical strength and stiffness at the contralateral cortical bone within 4 weeks of treatment. Taken together, the data presented here underscore the therapeutic potential of targeting CaMKK2 to promote efficacious and rapid healing of bone fractures and as a mechanism to strengthen normal bones. © 2018 American Society for Bone and Mineral Research.
(© 2018 American Society for Bone and Mineral Research.)
Databáze: MEDLINE
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