Osteoporosis, a disease characterized by the systemic loss of bone mass and strength resulting in fragility fractures, is rapidly poised to become a major public health threat in the United States. Osteoporosis results from imbalances in bone remodeling, a process characterized by osteoblast-mediated bone synthesis and osteoclast-mediated bone resorption. Because osteoporosis is fairly asymptomatic, and is often detected only after the patient has sustained significant bone erosion, therapies aimed at restoring the eroded bone are equally important as those that target bone resorption. However, unlike the highly efficient repertoire of anti- resorptive drugs that form the mainstay of the current anti-osteoporosis therapy, drugs that stimulate bone formation remain largely underdeveloped. Hence there is a critical need for novel therapeutic targets that will stimulate osteoblast-mediated bone accrual together with the inhibition of osteoclastic bone resorption. Our preliminary studies identify Ca2+/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) as one such target as its inhibition positively impacts anabolic pathways and negatively impacts catabolic pathways of bone remodeling. Mice null for CaMKK2 possess enhanced trabecular bone mass in their long bones, along with significantly higher numbers of osteoblasts and fewer multinuclear osteoclasts. Moreover, its inhibition offers protection from ovariectomy-induced and age-associated osteoporosis in mice. The proposed studies will enable us to define the precise mechanism by which CaMKK2 regulates osteoblast and osteoclast differentiation and devise potential strategies of its inhibition in the treatment of osteoporosis. Development of CaMKK2 inhibition as a new generation therapeutic target that promotes robust bone mass accrual while inhibiting resorption will represent a major breakthrough in anti-osteoporosis treatment.

Public Health Relevance

With a rapidly aging baby boomer population, osteoporosis presents a significant medical and socioeconomic problem in the United States. The current repertoire of anti-osteoporosis drugs though highly effective in halting bone loss does not stimulate bone mass accrual, revealing a critical need for therapies that stimulate bone growth. In this application, we propose in-depth investigations into the development of a Ca2+/calmodulin-dependent protein kinase family member as a new generation therapeutic target that promotes robust bone mass accrual while inhibiting bone loss, representing a major breakthrough in anti- osteoporosis treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR068332-05
Application #
9761835
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Nicks, Kristy
Project Start
2015-09-18
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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Sankar, Uma; Pritchard, Zachary J; Voor, Michael J (2016) Micro-computed tomography assisted distal femur metaphyseal blunt punch compression for determining trabecular bone strength in mice. J Biomech 49:1233-1237