Document text
Principal Investigator: EDWARD M. GREENFIELD
Organization: INDIANA UNIVERSITY INDIANAPOLIS
Fiscal Year: 2024
Award: $419,487
Funding agency: National Institute on Aging
ABSTRACT
Age-related trabecular bone loss begins in young adulthood and leads to increased rates of osteoporosis and
fractures in elderly men and women. It is fastest in vertebrae, where it is ~2-fold faster in women than in men,
and then accelerates in post-menopausal women. Stimulation of cAMP/PKA signaling by intermittent Parathyroid
Hormone-like (iPTH) drugs (teriparatide or abaloparatide) is the only FDA-approved osteoporosis therapy that
acts by increasing anabolic bone formation rather than by decreasing bone resorption. However, not all patients
respond, therapy is limited to 24 months, and the anabolic effects are not maintained after cessation. Moreover,
iPTH therapy requires daily injection and is extremely expensive (~$30,000/year). We previously discovered that
knockdown or deletion of Protein kinase inhibitor (Pkig) increases the anabolic processes induced by PTH/PKA
in vitro. Targeting PKI might therefore increase the magnitude of response, or the percent of patients who
respond, to iPTH therapy. Because the in vivo roles of PKI and the other two PKI family members were
previously unknown, we generated Pkig-/- mice. Our preliminary results indicate that genetic deletion of Pkig
overcomes both the age-related loss of bone volume and the age-related decline in skeletal healing.
Our long-term goal is therefore to determine whether PKI is a potential therapeutic target, either alone or in
combination with iPTH, to overcome age-related bone loss, the age-related decline in skeletal healing, and/or
post-menopausal bone loss. Our overall hypothesis is that PKI mediates age-related bone loss and the
age-related decline in skeletal healing by regulating the balance between osteogenesis and adipogenesis in a
sex- and skeletal site-dependent manner. The overall hypothesis will be tested by the following Aims:
Aim 1: Determine whether the effects of Pkig deletion on bone homeostasis depend on age, skeletal site, sex,
and/or iPTH therapy.
Aim 2: Determine mechanisms that are critical for regulation of age-related bone loss by PKI.
Aim 3: Determine whether Pkig deletion (either alone or in combination with iPTH) overcomes the age-related
decline of fracture healing and/or ovariectomy (OVX)-induced bone loss.
Terms: <21+ years old><3'5'-cyclic ester of AMP><Acceleration><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adult><Adult Human><Adult females><Adult women><Affect><Age><Age-Related Bone Loss><Apoptosis><Apoptosis Pathway><Autoregulation><Body Tissues><Bone 4-Carboxyglutamic Protein><Bone Formation><Bone Gla Protein><Bone Resorption><Bone gamma-Carboxyglutamic Acid Protein><CRE Recombinase><Cancellous bone><Cell Communication and Signaling><Cell Signaling><Cyclic AMP><Cyclic AMP-Dependent Protein Kinases><Drugs><Elderly man><Elderly woman><Enterobacteria phage P1 Cre recombinase><Equilibrium><FDA approved><Family member><Female><Females in adulthood><Forteo><Fracture><Fracture Healing><Future><Genetic><Goals><Homeostasis><In Vitro><Injections><Intracellular Communication and Signaling><LoxP-flanked allele><Mediating><Medication><Mice><Mice Mammals><Murine><Mus><Oophorectomy><Osteoblasts><Osteocalcin><Osteoclastic Bone Loss><Osteogenesis><Osteoporosis><Ovariectomy><PKA><PTH gene><Parathyrin><Parathyroid Hormone><Patients><Perimenopausal Bone Loss><Persons><Pharmaceutical Preparations><Physiological Homeostasis><Post-Menopausal Osteoporosis><Post-Menopause><Post-menopausal Period><Postmenopausal Bone Loss><Postmenopausal Osteoporosis><Postmenopausal Period><Postmenopause><Process><Programmed Cell Death><Proliferating><Protein Kinase A><Regulation><Role><Signal Transduction><Signal Transduction Systems><Signaling><Site><Teriparatide><Testing><Tissues><Vertebrae><Vertebral><Vitamin K-Dependent Bone Protein><Vitamin K-Dependent Calcium-Binding Protein><Woman><Women in adulthood><adenosine 3'5' monophosphate><adipogenesis><adult youth><adulthood><after menopause><age associated><age associated decline><age correlated><age dependent><age dependent decline><age linked><age related><age related decline><age specific><age-associated bone loss><aged mice><aged mouse><ages><bacteriophage P1 recombinase Cre><balance><balance function><biological signal transduction><bone><bone fracture><bone fracture healing><bone fracture repair><bone loss><bone loss with aging><bone tissue formation><cAMP><cAMP-Dependent Protein Kinases><decline with age><drug/agent><elderly mice><female gonadectomy><floxed><floxed allele><following menopause><fracture repair><hPTH (1-34)><healing><in vivo><knock-down><knockdown><lipid biosynthesis><lipogenesis><men><old mice><osteoprogenitor><osteoprogenitor cell><parathormone><past menopause><post-menopausal><postmenopausal><postmenopausal status><progenitor><promoter><promotor><protein kinase inhibitor><response><senescence><senescent><sex><skeletal><social role><spine bone structure><substantia spongiosa><substantia trabecularis><therapeutic target><trabecular bone><young adult><young adulthood>