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

Justin N. Williams, Anuradha Valiya Kambrath, Roshni B. Patel, Kyung Shin Kang, Elsa Mével, Yong Li, Ying Hua Cheng, Austin J. Pucylowski, Mariah A. Hassert, Michael J. Voor, Melissa Kacena, William R. Thompson, Stuart J. Warden, David Burr, Matthew Allen, Alexander Robling, Uma Sankar

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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 Ca2+/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.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Fracture Healing
Hedgehogs
Osteogenesis
Protein Kinases
Phosphotransferases
Bone and Bones
Bone Fractures
Bony Callus
Pharmacology
Closed Fractures
Calcium-Calmodulin-Dependent Protein Kinases
Bone Matrix
Femoral Fractures
Homeobox Genes
Therapeutics
Chondrocytes
Collagen Type I
Osteoblasts
Mesenchymal Stromal Cells
Health Care Costs

Keywords

  • ANABOLICS
  • ANIMAL MODELS
  • INJURY/FRACTURE HEALING
  • ORTHOPAEDICS
  • PRECLINICAL STUDIES
  • THERAPEUTICS

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Inhibition of CaMKK2 Enhances Fracture Healing by Stimulating Indian Hedgehog Signaling and Accelerating Endochondral Ossification. / Williams, Justin N.; Kambrath, Anuradha Valiya; Patel, Roshni B.; Kang, Kyung Shin; Mével, Elsa; Li, Yong; Cheng, Ying Hua; Pucylowski, Austin J.; Hassert, Mariah A.; Voor, Michael J.; Kacena, Melissa; Thompson, William R.; Warden, Stuart J.; Burr, David; Allen, Matthew; Robling, Alexander; Sankar, Uma.

In: Journal of Bone and Mineral Research, 01.01.2018.

Research output: Contribution to journalArticle

Williams, JN, Kambrath, AV, Patel, RB, Kang, KS, Mével, E, Li, Y, Cheng, YH, Pucylowski, AJ, Hassert, MA, Voor, MJ, Kacena, M, Thompson, WR, Warden, SJ, Burr, D, Allen, M, Robling, A & Sankar, U 2018, 'Inhibition of CaMKK2 Enhances Fracture Healing by Stimulating Indian Hedgehog Signaling and Accelerating Endochondral Ossification', Journal of Bone and Mineral Research. https://doi.org/10.1002/jbmr.3379
Williams, Justin N. ; Kambrath, Anuradha Valiya ; Patel, Roshni B. ; Kang, Kyung Shin ; Mével, Elsa ; Li, Yong ; Cheng, Ying Hua ; Pucylowski, Austin J. ; Hassert, Mariah A. ; Voor, Michael J. ; Kacena, Melissa ; Thompson, William R. ; Warden, Stuart J. ; Burr, David ; Allen, Matthew ; Robling, Alexander ; Sankar, Uma. / Inhibition of CaMKK2 Enhances Fracture Healing by Stimulating Indian Hedgehog Signaling and Accelerating Endochondral Ossification. In: Journal of Bone and Mineral Research. 2018.
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AU - Kambrath, Anuradha Valiya

AU - Patel, Roshni B.

AU - Kang, Kyung Shin

AU - Mével, Elsa

AU - Li, Yong

AU - Cheng, Ying Hua

AU - Pucylowski, Austin J.

AU - Hassert, Mariah A.

AU - Voor, Michael J.

AU - Kacena, Melissa

AU - Thompson, William R.

AU - Warden, Stuart J.

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