Session Type: Abstract Submissions (ACR)
Patients with osteoporosis and the elderly have an increased risk of bone fracture. Currently, no biomarker is available to assess bone healing status in fracture patients. Although a coordinated interaction between osteoclasts (OC) and osteoblasts (OB) is required for bone repair after fracture, the molecular mechanisms underlying bone repair are not well understood. We previously demonstrated that DC-STAMP (Dendritic Cell-Specific Transmembrane protein), a 7-pass transmembrane protein essential for cell-to-cell fusion during OC differentiation, is a biomarker of OC precursors (OCP). Intriguingly, an elevated OCP frequency was observed that correlated with an increased frequency of circulating DC-STAMP+ cells in two bone fracture patients 8-week post-fracture. Thus, we hypothesized that multinucleated OC are essential for optimal bone repair and that the frequency of DC-STAMP+cells may serve as biomarkers to assess bone healing. The function of OB and OC in bone fracture and healing was dissected in the DC-STAMP knock-out (KO) mice which lack mature multinucleated OC.
OB differentiation, bone healing and bone quality were compared between gender- and age-matched wild-type and DC-STAMP KO littermates. OB differentiation was assessed by mineral nodules and ALP+ cells (OB marker) quantification. Bone fracture and callus formation were examined by uCT, x-ray and histology analysis. Bone quality was tested by biomechanical assays including 3-point bending and torsion test. The presence of DC-STAMP+ cells at fresh fracture sites and at healed regions was examined by immunofluorescence. The frequency of circulating DC-STAMP+cells in two bone fracture patients was analyzed by flow cytometry.
In mice, DC-STAMP+ cells were identified at fresh fracture sites and in blood vessels traversing surrounding tissues. DC-STAMP KO mice demonstrated decreased OB differentiation (WT vs. KO: 0.6 +/- 0.1 vs. 0.1 +/- 0, p=0.05 and 0.8 +/- 0.2 vs. 0.15 +/- 0.1 cm2/well, p=0.01 for mineral nodules and Alp+ cells, respectively) and delayed bone healing (WT and KO mice healed on wk3 and wk6, respectively, post-fracture). Tibias from KO mice have a higher stiffness as demonstrated by torsional analysis (1226 +/- 308 vs. 1762 +/- 527 N/mm for WT and KO, p=0.1). In humans, two bone fracture patients had a significant increase in the frequency of circulating DC-STAMP+cells and elevated OCP frequency (healthy, 185 +/- 62; patients, 1,250 +/- 65 per 10e6 monocytes).
These findings suggest that (1) DC-STAMP is involved in bone healing based on the presence of DC-STAMP+ cells surrounding the fracture sites; (2) Both OB and OC are required for an efficient healing of bone fractures; (3) Elevation of OCP frequency and the number of circulating DC-STAMP+ cells in two patients with recent fracture suggest that an increased DC-STAMP+ cell frequency might serve as a surrogate marker reflecting active ongoing bone remodeling during the course of bone repair. Our data suggest that in addition to its critical role in regulating OC development, DC-STAMP is also involved in OB differentiation and bone repair. Thus, DC-STAMP has potential to serve as a bone-repair biomarker and therapeutic target to promote fracture healing.
Y. G. Chiu,
T. R. Sheu,
C. T. Ritchlin,
Eli Lilly and Company,
Eli Lilly and Company,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dc-stamp-modulates-osteoblast-differentiation-and-regulates-bone-repair/