Bad to the Bone: Age-related Increases in Serum SDF-1 Leads to Bone Loss with Age

  • Hill, William D, (PI)

Project: Research project

Description

Osteoporosis is under-reported in men and may be present in up to 31% of male VA patients. Further, it is
among the most debilitating disorders for women - who make up an increasingly larger share of our veteran
population. Hip and vertebral fractures, major risks with osteoporosis, lead to loss of independence, pain, even
potentially serious cardiac and brain morbidities, as well as increased mortality. Our main hypothesis is that the
cytokine stromal-derived factor 1 (SDF-1, aka CXCL12) is increased in the peripheral circulation with age and
contributes to age-associated bone loss. In the peripheral blood SDF-1 is rapidly converted to an N-terminal
endopeptidase-cleaved form by the circulating dipetidlylpeptidase CD26 (dipetidlylpeptidase 4, DPP4). The
cleaved form of SDF-1 binds to and blocks the SDF-1 receptor CXCR4, but does not activate it. It becomes in
effect an inhibitor. Because of the quick alteration of SDF-1 by DPP4, but its slower total breakdown and
removal, our research suggests the majority of the SDF-1 in the blood and bone marrow is of the
inactive/inhibitory form. Part of our hypothesis is that if the level of the inactive form rises slowly, and stays up
with aging, then CXCR4 signaling is reduced long-term and this will have a negative impact on bone, reducing
the number of BMSCs and reducing bone formation. There is increasing evidence that CXCR4 signaling is
needed for BM mesenchymal stem cells (BMSCs) to maintain a progenitor cell population and to initiate and
support osteogenesis. Importantly, preclinical murine studies from our laboratory have shown that circulating
levels of total SDF-1, including the DPP4-cleaved form, increase with age in mice and that experimentally
increasing the plasma level of DPP4-cleaved SDF-1 in young mice reduces bone formation serum markers
and significantly decreases trabecular bone volume and bone density. This led to a funded NIH PO1 grant to
determine the role of SDF-1 isoforms in the regulation of murine bone formation with age. The research studies
proposed here are to see if our hypotheses and observations in mice are true in humans: We propose to test
the novel hypothesis that in humans increased DPP4-cleaved SDF-1 isoforms are important factors in age-and
disease-associated bone loss. We propose to assess the levels of circulating, and bone marrow, SDF-1
(DPP4-cleaved and non-cleaved) levels, DPP4 activity, and the effects of these isoforms on human BMSC's
osteogenic activity in vitro and bone formation and quality/density in vivo. We will measure SDF-1 isoforms
along with DPP4 in the serum and bone marrow of patients of different ages, and correlate this with their bone
density and volume, as well as serum markers of bone formation or breakdown. We will also determine if there
are changes in these SDF-1 and DPP4 parameters in patients with osteoporosis relative to age-matched
controls. We further propose to determine the effects on bone formation of FDA-approved drugs in use for
diabetic therapy, which act by regulating DPP4 activity (e.g. sitaglitin). We will determine if diabetic patients
receiving treatment with these DPP4 inhibitors show improved bone formation compared to controls. Finally,
we will use isolated human patient BMSCs to determine if DPP4 cleaved SDF-1 reduces BMSC cell survival,
proliferation, and osteogenic potential. Additionally, these human BMSCs will be assessed to determine if there
are age-associated changes in miRNAs targeting the SDF-1 axis and osteogenic genes. We will deteremine
experimentally if such miRNAs effect BMSC cell fate. This work could rapidly lead to clinical trials of already
FDA approved DPP4 inhibitors as a novel pro-bone remodeling treatment for osteoporosis as a replacement,
or enhancement, of current problematic anti-remodeling therapies. In follow up studies, acute inhibition of
DPP4 may also have value in increasing bone repair rates via increasing the active form of SDF-1 to increase
stem cell homing and osteogenic induction following fracture, or other truamatic injury to bone, a critical need
for the VA and DoD. Longer-term this work opens the potential to use regulation of specific miRNAs to regulate
the osteogenic environment for BMSCs with age and to prevent osteoporosis.
StatusFinished
Effective start/end date1/1/1412/31/17

Funding

  • National Institutes of Health
  • National Institutes of Health

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Mesenchymal Stromal Cells
Osteogenesis
Bone and Bones
Osteoporosis
Serum
MicroRNAs
Protein Isoforms
Bone Marrow
CXCR4 Receptors
Organized Financing
Bone Remodeling
Age Factors
Hip Fractures
Therapeutics
Research
Bone Density
Cell Survival
Stem Cells
Biomarkers
Cell Proliferation

ASJC

  • Medicine(all)