Cathepsin G Enhances Mammary Tumor–Induced Osteolysis by Generating Soluble Receptor Activator of Nuclear Factor-κB Ligand

Abstract

Breast cancer commonly causes osteolytic metastases in bone, a process that is dependent on tumor-stromal interaction. Proteases play an important role in modulating tumorstromal interactions in a manner that favors tumor establishment and progression. Whereas several studies have examined the role of proteases in modulating the bone microenvironment, little is currently known about their role in tumor-bone interaction during osteolytic metastasis. In cancer-induced osteolytic lesions, cleavage of receptor activator of nuclear factor-KB ligand (RANKL) to a soluble version (sRANKL) is critical for widespread osteoclast activation. Using a mouse model that mimics osteolytic changes associated with breast cancer-induced bone metastases, we identified cathepsin G, cathepsin K, matrix metalloproteinase (MMP)-9, and MMP13 to be proteases that are up-regulated at the tumor-bone interface using comparative cDNA microarray analysis and quantitative reverse transcription-PCR. Moreover, we showed that cathepsin G is capable of shedding the extracellular domain of RANKL, generating active sRANKL that is capable of inducing differentiation and activation of osteoclast precursors. The major source of cathepsin G at the tumor-bone interface seems to be osteoclasts that up-regulate production of cathepsin G via interaction with tumor cells. Furthermore, we showed that in vitro osteoclastogenesis is reduced by inhibition of cathepsin G in a coculture model and that in vivo inhibition of cathepsin G reduces mammary tumor-induced osteolysis. Together, our data indicate that cathepsin G activity at the tumor-bone interface plays an important role in mammary tumor-induced osteolysis and suggest that cathepsin G is a potentially novel therapeutic target in the treatment of breast cancer bone metastasis. [Cancer Res 2008;68(14):5803-11]

Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE2, and MMP-13 expression

“…RANKL belongs to the tumor necrosis factor (TNF) family and may be detected as a secreted factor as a consequence of proteolytic cleavage. As a ligand, RANKL interacts with its receptor RANK, a type I transmembrane [34,35] . RANKL is becoming a novel target molecule for anti-RA remedy.…”

Differential proteomic analysis of a human breast tumor and its matched bone metastasis identifies cell membrane and extracellular proteins associated with bone metastasis

“…Major down-regulated proteins in the bone metastatic lesion include apolipoprotein E, whose deficiency has been reported in the context of a reduction of bone formation 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 osteolysis 53 , resistin, which is known to increase osteoclastogenesis 54 , and prothrombin, which is overexpressed during osteoclastogenesis in rodents. 55 Among the proteins expressed in the bone metastase and the breast primary lesion, we noticed that the small leucine-rich proteoglycan (SLRP) family was well represented.…”

“…52 28 CTSG Cathepsin G ↑ Cathepsin G activity at the tumor-bone interface plays an important role in mammary tumor-induced osteolysis. 53 …”

Cathepsin G Recruits Osteoclast Precursors via Proteolytic Activation of Protease-Activated Receptor-1

“…The ratelimiting step of this cycle is the signaling that occurs between osteoblasts and osteoclasts because this requires cell to cell contact to bring receptor activator of nuclear factor-nB (RANK) ligand (RANKL) on the surface of osteoblasts and RANK on the surface of osteoclast precursors into contact. Our recent data show that this requirement can be bypassed via cleavage of RANKL from the cell surface of osteoblasts by cathepsin G, generating soluble RANKL (sRANKL) that relieves the necessity of cell-cell contact and allows widespread osteoclast activation and enhanced osteolysis (4). Cathepsin G expression is up-regulated at the tumor-bone interface of mammary tumor-induced osteolytic lesions (4).…”

“…Our recent data show that this requirement can be bypassed via cleavage of RANKL from the cell surface of osteoblasts by cathepsin G, generating soluble RANKL (sRANKL) that relieves the necessity of cell-cell contact and allows widespread osteoclast activation and enhanced osteolysis (4). Cathepsin G expression is up-regulated at the tumor-bone interface of mammary tumor-induced osteolytic lesions (4). However, even with the increased generation of sRANKL, there must be continuous recruitment of osteoclast precursors that can become activated for osteolysis to continue to occur.…”