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The Role of DC-STAMP in Osteoclastogenesis

Bone remodeling is a dynamic and complex process finely orchestrated by cell interactions among osteoblast, T, B and natural killer cells. The first phase of bone remodeling requires activation of monocytes/macrophages by M-CSF and the receptor activator nuclear factor-kappa B ligand (RANKL) to initiate cell-cell contact and induce the formation of multinucleated osteoclasts (OCs). Activated OCs attach to bone tissue releasing proteases and acid to dissolve and resorb bone. During the second phase, osteoblasts secrete a soluble decoy receptor (osteoprotegerin, OPG) to block RANK/RANKL interaction and prevent osteoclast differentiation. A defect in osteoclast or osteoblast activation results in gain (osteopetrosis) or loss of bone (osteoporosis).

Osteoporosis is one of the most common causes of hospitalization in men and women with fragile bones. Patients with osteoporosis usually suffer extreme pain and immobility. Therefore, new treatments are needed to prevent bone fractures and increase the quality of life in patients with this disease. Our research is focused to 1) elucidate the signaling pathways activated by DC-STAMP, a transmembrane protein that is required for optimal OC differentiation, and 2) test whether neutralization of DC-STAMP function with antibodies prevents bone loss in experimental models of Rheumatoid Arthritis (RA).

  1. Does blockade of DC-STAMP decrease OC differentiation in preclinical models of RA?
    Our main goal is to underline the cellular and molecular pathways that are affected by DC-STAMP expression and/or activation during the onset of RA in TNF tg and KRN mouse model. We recently showed that the absence of DC-STAMP in TNF tg modulates bone erosion and increases mouse survival. We also found that DC-STAMP expression on stromal cells is required to modulate inflammation in secondary lymphoid organs from TNF Tg mice.
    DC-STAMP on Hematopoietic Cells
    DC-STAMP on hematopoietic cells decreases bone resorption in TNF Tg mice. Microcomputed tomography (µCT) of trabecular bone from 7-month old mice reconstituted with TNT tg, wild type or DC-STAMP-/- bone marrow.
  2. Define the value of DC-STAMP as a marker for psoriasis arthritis.
    We have reported high expression level of DC-STAMP in patients with psoriasis, who eventually may progress to psoriatic arthritis. Thus, we are interested to define whether DC-STAMP, could be used as a marker to predict the progression from psoriasis to psoriatic arthritis. In addition, we are analyzing human samples to understand the cellular and molecular mechanisms implicated in the transition from psoriasis to psoriatic arthritis.
    DC-STAMP Effect on PBMC
    PBMC were first stained with antibodies against CD3, D19, CD16. Then one sample was incubated with isotype control antibodies and the other with anti-DC-STAMP. CD3-CD19-CD16+DC-STAMP+ cells were enumerated by flow cytometry.