Osteoclast secreted chemokine and uses thereof

Details Osteoclast secreted chemokine and uses thereof Osteoclast secreted chemokine and uses thereof

2001-06-19

2003-05-20

Kemmerer, Elizabeth (Department: 1646)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C424S085100

Reexamination Certificate

active

06566333

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of biochemical endocrinology and regulation of bone formation and degradation. More specifically, the present invention relates to the regulation of osteoblast function by the osteoclast-secreted chemokine-like protein mim-1 and uses thereof.
2. Description of the Related Art
Osteoclasts are multinucleated cells formed by fusion of precursors derived from pleuripotential hematopoietic stem cells (
1
) that circulate in the monocyte fraction (
2
,
3
). Differentiation of the precursors into osteoclasts is a complex process that requires both M-CSF and RANKL (ODF, osteoclast differentiation factor; also known as TRANCE) (
4
,
5
). The mechanism(s) by which osteoclastic precursors are recruited to an area of bone resorption, establish and differentiate into mature osteoclasts is a complex process that is still not fully understood.
Mature osteoclasts are terminally differentiated cells and while it is clear that M-CSF and RANKL are essential for differentiation of osteoclasts, additional osteoclast-inductive agents or synergistic effectors of RANKL are likely to be important in the development of active mature osteoclasts (
6
,
7
). In fact, RANKL/TRANCE is not bone-specific since it was first cloned as a tumor necrosis factor (INF) related activation-induced cytokine (TRANCE) in T-cell hybridomas suggesting a potential role in immune function (
8
).
Communication via a variety of signaling molecules has long been proposed as a key component in the homeostatic signaling process between osteoclasts and osteoblasts (
9
,
10
). Osteoclasts respond to numerous factors that are derived from bone or the bone microenvironment including, among others, IL-1, IL-6, TNF&agr; and TGF-&bgr;, and osteoprotegrin (
6
,
7
,
10
-
13
). Under conditions of normal bone turnover, bone resorption is followed by new bone synthesis. The mechanisms regulating recruitment of osteoblast precursors into areas is recently degraded are poorly understood, but presumably involve a signaling pathway between osteoclasts and osteoblasts (
14
).
The prior art is deficient in methods of regulating the secretion of a chemokine-like protein expressed specifically by cells of hematopoietic origin, like osteoclasts, so as to manipulate a signaling pathway that may be involved in regulating recruitment of osteoblast precursor cells to areas of recent bone resorption. The present invention fulfills this long-standing need and desire in the art.
SUMMARY OF THE INVENTION
Mim-1 is a protein reported to be expressed specifically by cells of hematopoietic origin (
15
), which includes osteoclasts. Mim-1 is distinct from, but homologous with, the neutrophil chemokine protein, LECT2, and is an abundant protein in osteoclasts. In addition, mim-1 is secreted in a time dependent manner in vitro. Furthermore, secretion of mim-1 is stimulated in a PMA concentration dependent manner. Secretion of mim-1 precedes the largest increase in PMA stimulated bone resorption by isolated osteoclasts. Immunofluorescence microscopy demonstrated that both avian osteoclasts and human osteoclast-like cells express mim-1, but not mesenchymal stem cells (which includes osteoblast precursors). Mim-1 may be a key signaling protein secreted by osteoclasts that regulates recruitment and/or differentiation of osteoblast precursor cells, thereby providing an essential mechanism for regulating the mass and structural integrity of bone.
The present invention is drawn to methods of inducing recruitment and proliferation of osteoblasts and increased bone resorption by osteoclasts following secretion of mim-1. Generally, the mim-1 protein has the sequence of SEQ ID NO. 8 or a fragment thereof.
In another aspect of the present invention, there is provided methods of inducing bone resorption activity of osteoclasts, inducing recruitment and proliferation of osteoblasts, and inducing new bone synthesis in an individual by mim-1 protein. Generally, the mim-1 protein has the sequence of SEQ ID NO. 8 or a fragment thereof.


REFERENCES:
patent: 97065715 (1997-10-01), None
Yamada et al, p33, an endogenous target protein for arginine-specific ADP-ribosyltransferase in chicken polymorphonuclear leukocytes, is highly homologous to mim-1 protein (myb-induced myeloid protein-1). FEBS lett. 311:203-205, 1992.*
Swiss-Prot, Accession No. P08940, Jul. 15, 1999.*
Choi et al, A-Geneseq, Accession No. AAM52000, Mar. 15, 2002.

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