Document text
Principal Investigator: Robert Nissenson
Organization: VETERANS AFFAIRS MED CTR SAN FRANCISCO
Fiscal Year: 2024
Funding agency: Veterans Affairs
The maintenance of healthy bones in adults requires coordinated bone turnover where bone formation is
closely coupled to bone resorption, allowing bone renewal with the maintenance of bone mass. Uncoupling
of bone formation and bone resorption underlies the loss of bone mass seen in a variety of conditions
including aging, the menopause, and various inflammatory disorders such as rheumatoid arthritis (RA).
These disorders are generally associated with enhanced bone resorption accompanied by rates of bone
formation that are inadequate for the level of resorption. Anti-resorptive therapies have been the traditional
approach for treating patients with low bone mass in these conditions, but it is increasingly recognized that
anabolic therapies that enhance bone formation constitute an important alternative strategy. Previous
studies have identified that inhibitory G protein (Gi) signaling in osteoblast lineage cells suppresses bone
formation and is an important driver of age-related bone loss in females, but the factors that are upstream
of this signaling pathway are unknown. Suppression of canonical Wnt signaling in osteoblast lineage cells
is also linked to reduced bone formation. The present study will use a variety of mouse models to test the
hypothesis that progranulin (PGRN), an inflammation-associated factor produced by macrophages and
implicated in age-related bone loss, is a critical upstream regulator of inflammatory cytokine production
and that PGRN-mediated cytokine production promotes bone loss through activation of Gi signaling and
suppression of canonical Wnt signaling in osteoblast lineage cells. This hypothesis will be tested in three
specific aims. In Specific Aim 1, the role of PGRN in bone marrow macrophage (BMM)-regulated bone
formation will be explored. To accomplish this, we will determine whether alternations in the population of
BMMs accounts for promotion of bone resorption by PGRN; whether expression of PGRN reduces the pro-
osteogenic activity of BMMs; and whether transplantation of BMMs from PGRN-deficient mice can protect
or reverse bone loss in adult female mice. Specific Aim 2 will address the role of suppression of anabolic
signaling pathways in the negative effects of PGRN on bone formation. The role of the canonical Wnt
pathway will be investigated in vivo in mice with targeted deletion of Ctnnb1, the gene encoding b-catenin,
and will be investigated in vitro in osteoblast lineage cells lacking expression of PGRN. The ability of PGRN
to inhibit Gs/cyclic AMP signaling will be assessed in vitro in cultured osteocytes and in vivo in its ability to
limit the anabolic response to intermittent PTH administration. Specific Aim 3 is a translational aim in which
we will explore the role of PGRN in mediating bone loss in two disorders associated with inflammation-
rheumatoid arthritis (RA) and estrogen deficiency-induced osteoporosis. We will determine whether PGRN
deficient mice are protected from bone loss after ovariectomy (OVX) and from systemic bone loss and
local joint erosion in the K/BxN serum transfer model of RA. The effect of PGRN deletion on the
inflammatory phenotype of BBMs in response to serum transfer and OVX will also be assessed. Bone
marrow transplantation studies will be carried out to determine whether PGRN-deficient BBMs can rescue
the skeletal pathology associated with OVX and RA. Successful completion of the studies in this proposal
will illuminate the pathogenesis of bone disease associated with inflammatory disorders such as RA and
postmenopausal osteoporosis. Defining the details of this relationship will lead to the identification of new
therapeutic targets for preventing or reversing bone loss in these conditions.
Terms: <(TNF)-α><21+ years old><3'5'-cyclic ester of AMP><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adult><Adult Human><Adult females><Adult women><Affect><Age-Related Bone Loss><Aging><Amyloid><Amyloid Substance><Anabolism><Atrophic Arthritis><Automobile Driving><Beta Cadherin-Associated Protein><Beta-1 Catenin><Blood Serum><Bone Diseases><Bone Formation><Bone Formation Inhibition><Bone Marrow><Bone Marrow Grafting><Bone Marrow Reticuloendothelial System><Bone Marrow Transplant><Bone Marrow Transplantation><Bone Resorption><Bone Resorption Stimulation><CBP-30><CBP-35><CBP35><CUL-2><Cachectin><Carbohydrate-Binding Protein 35><Cell Body><Cell Communication and Signaling><Cell Lineage><Cell Signaling><Cells><Coupled><Cyclic AMP><Defect><Deficiency Diseases><Disease><Disorder><Epsilon-Binding Protein><Estrogen deficiency><Female><Females in adulthood><Fracture><G-Proteins><GTP-Binding Proteins><GTP-Regulatory Proteins><Galectin 3><Gene Deletion><Gene Expression><Genes><Genetic><Genetic Suppression><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><HL-29><IgE Binding Protein><IgEBP><In Vitro><Inflammation><Inflammatory><Injury><Innate Immune Response><Innate Immune System><Innate Immunity><Intracellular Communication and Signaling><Joints><K/BxN><K/BxN model><KBxN><KO mice><Knock-out Mice><Knockout Mice><Knowledge><L-29 Lectin><L-31><L-34><L30 Lectin><LGALS3><Link><Mac-2 Antigen><Macrophage><Macrophage-2 Antigen><Macrophage-Derived TNF><Maintenance><Marrow Transplantation><Mediating><Menopause><Mice><Mice Mammals><Modeling><Monocyte-Derived TNF><Murine><Mus><Musculoskeletal Diseases><Mφ><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Null Mouse><Oophorectomy><Osteoblasts><Osteoclastic Bone Loss><Osteoclasts><Osteocytes><Osteogenesis><Osteoporosis><Ovariectomy><PC cell-derived growth factor><PCDGF><PGRN gene><PGRN protein><PRO2286><Pathogenesis><Pathology><Pathway interactions><Patients><Perimenopausal Bone Loss><Phenotype><Play><Population><Post-Menopausal Osteoporosis><Postmenopausal Bone Loss><Postmenopausal Osteoporosis><Production><Progranulin><Reporting><Rheumatoid Arthritis><Role><Serum><Services><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Skeletal Development><Skeleton><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Transplantation><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Veterans><WNT Signaling Pathway><WNT signaling><Women in adulthood><adenosine 3'5' monophosphate><adulthood><age-associated bone loss><beta catenin><biological signal transduction><biosynthesis><bone><bone disorder><bone erosion><bone fracture><bone loss><bone loss with aging><bone mass><bone tissue formation><bone turnover><cAMP><cytokine><deficiency in estrogen><driving><female gonadectomy><fracture risk><gene deletion mutation><granulin precursor><in vivo><injuries><interest><mouse model><murine model><musculoskeletal disorder><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><osteoclastogenesis><osteogenic><pathway><prevent><preventing><progenitor><progranulin gene><progranulin protein><repair><repaired><response><rheumatic arthritis><skeletal><skeletons><social role><therapeutic target><transplant><β-catenin>