Summary
Sickle cell disease (SCD) is a hemoglobinopathy associated with severe bone abnormalities including
osteoporosis. Eighty percent of SCD adults have low bone mineral density (BMD) that is independent of risk
factors such as age, gender, and menopausal status, suggesting the etiology of osteoporosis in SCD differs from
the general population. Proposed contributing factors to bone loss in SCD include marrow hyperplasia secondary
to chronic anemia, inflammation, ischemia, and vitamin D deficiency. However, the mechanisms of bone loss in
SCD subjects has not been fully investigated, and there are no targeted therapies. Hormonal fibroblast growth
factor 23 (FGF23), which controls phosphate homeostasis and has direct and indirect effects on bone
mineralization, is reported to be increased in human anemia. Based on our exciting preliminary data showing
that increased serum FGF23 and hypophosphatemia in humanized Townes SCD mice, which are anemic
but not in renal failure, and that in vitro and in vivo FGF23 blockade partially rescues impaired
mineralization and improved reduced BMD in SCD mice, we posit that cross-talk involving bone marrow
erythropoiesis, kidney, and bone contributes to osteoporosis in SCD mice. Specifically, we posit that 1) sickling
of red blood cells and the resulting anemia causes increased erythropoietin production by the kidney, which
increases bone FGF23 production that impairs phosphate reabsorption; and 2) anemia-induced FGF23 results
in impaired osteoblast differentiation, mineralization, and bone strength in SCD mice due to hypophosphatemia
and pyrophosphate abnormalities via impaired sodium phosphate transporters PIT1 and PIT2 signaling in bone.
Furthermore, increased FGF23 reduces PIT1 signaling that can interfere with erythrocyte differentiation, further
perpetuating the anemic state. To test our hypotheses, we propose the following Specific Aims: Aim 1: Examine
the molecular mechanisms by which FGF23 contributes to phosphate wasting in SCD Mice; Aim 2: Assess the
molecular mechanism by which FGF23 contributes to impaired bone mineralization in SCD mice; and Aim 3:
Determine whether FGF23 neutralizing antibody modulates the anemia phenotype of SCD mice. Our proposed
studies may identify FGF23 as a novel contributor to the pathogenesis of bone loss and anemia in SCD mice.
Since the FGF23Ab is now FDA approved for the treatment of X-linked hypophosphatemia, it may also be a
useful therapy to prevent bone loss and improve anemia in human SCD in the future.