Background/Purpose:

Osteoclasts (OC) direct pathologic bone resorption in osteoporosis and inflammatory arthritis. We previously demonstrated that DC-STAMP (Dendritic Cell-Specific Transmembrane protein), a 7-pass transmembrane protein, is not only essential for cell fusion during osteoclastogenesis but mice that lack this molecule also show impaired osteoblast (OB) differentiation. OC precursors arise from CD14+DC-STAMP+ cells in humans and the frequency of CD11b+DC-STAMP+ cells correlates with the extent of bone erosion in the TNF-Tg arthritis model. A rapid recruitment of DC-STAMP+ mononuclear cells to bone fracture sites and delayed bone healing in DC-STAMP knock-out (KO) mice suggested that DC-STAMP may also modulate fracture repair.

Methods:

(1) To investigate the interplay between DC-STAMP+ cells and OB, we examined the recruitment of DC-STAMP+ cells to the vicinity of OB using a mouse strain (collagen-I cre ROSA-rtta TRE-LacZ) whose OB lineage cells can be traced by the blue LacZ expression. OB differentiation was evaluated with the CFU-ALP and bone nodule formation assays. To examine the role of DC-STAMP+ cells in arthritis progression, we (2) introduced one copy of DC-STAMP knockout locus into the TNF+ mouse line and examined the effect of DC-STAMP KO on OB & OC differentiation and arthritis development; and (3) re-constituted lethally irradiated TNF-Tg mice with bone marrows (BM) from WT or DC-STAMP KO donors and compared arthritis progression between the two groups.

Results:

(1) Histology analysis: TRAP+DC-STAMP+ cells were recruited to the vicinity of LacZ+ OB at the bone fracture sites, whereas OB/OC co-localization was never detected on intact bones without fractures. (2) Genetic analysis: introduction of one DC-STAMP KO locus into the TNF+ background resulted in three phenotypes: (a) bone erosion was less severe; Bone Volume/Total volume (BV/TV: 18.2±5.7 & 12.0±3.1 in TNF+DC-STAMP+/- & TNF+DC-STAMP+/+) mice; (b) 6/15 mice showed asymmetric arthritis, suggesting an alleviated arthritis symptom; (c) OB differentiation was impaired (CFU-f units/well: 112±8 & 225±10 for TNF+DC-STAMP+/- & TNF+DC-STAMP+/+). (3) Bone marrow re-constitution: the expression level of DC-STAMP in the adoptively-transferred cells was up-regulated in the TNF+ background (the mean fluorescence intensity (MFI) in TNF+ and TNF- recipients were 1,205±82 & 723±98, respectively). TNF+ mice that received DC-STAMP+/+ donor cells developed severe arthritis approximately one week earlier than those receiving the DC-STAMP-/- donor cells (deformation scores: 8.0±2.5 & 5.0±3.2 for DC-STAMP+/+ & DC-STAMP-/- donors, respectively, at week-4 post-adoptive transfer).

Conclusion:

Aggregation of DC-STAMP+ cells around OB at fracture sites suggests that DC-STAMP is involved in OB:OC interactions. Arrested OB differentiation in DC-STAMP+/-TNF-Tg mice confirms our initial observations that DC-STAMP is required for adequate OB function. Moreover, DC-STAMP expression level increased in the presence of elevated in vivo TNFa concentration. Collectively, our data indicate that arthritis pathogenesis and bone repair can be modulated by the gene copy number and expression level of DC-STAMP.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dendritic-cell-specific-transmembrane-protein-dc-stamp-modulates-bone-resorption-in-inflammatory-arthritis-and-fracture-repair/