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Abstract Number: 25

DC-STAMP Modulates Osteoblast Differentiation and Regulates Bone Repair

Yahui Grace Chiu1, Tzong-Ren Sheu2, Jinbo Li3, Dongge Li1, Michael Thullen2, Brendan Boyce4, Edward Puzas2 and Christopher T. Ritchlin5, 1Allergy, Immunology and Rheumatology, University of Rochester, Rochester, NY, 2Center for Musculoskeletal Research, University of Rochester, Rochester, NY, 3Pathology, University of Rochester, Rochester, NY, 4Pathology, University of Rochester, Rocehster, NY, 5Allergy Immunology & Rheumatology, University of Rochester Medical Center, Rochester, NY

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: bone biology, fractures, Osteoblasts, osteoclastogenesis and osteoclasts

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Session Information

Session Title: Biology and Pathology of Bone and Joint: Osteoclasts, Osteoblasts and Bone Remodeling

Session Type: Abstract Submissions (ACR)

Background/Purpose

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.

Methods

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.

Results

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).

Conclusion

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.


Disclosure:

Y. G. Chiu,
None;

T. R. Sheu,
None;

J. Li,
None;

D. Li,
None;

M. Thullen,
None;

B. Boyce,
None;

E. Puzas,
None;

C. T. Ritchlin,

Eli Lilly and Company,

9,

Eli Lilly and Company,

5.

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