Matrix metalloproteinase processing of PTHrP yields a selective regulator of osteogenesis, PTHrP1–17

Frieling, Jeremy S.; Shay, Gemma; Izumi, Victoria; Aherne, Sinéad; Saul, Richard G.; Budzevich, Mikalai M.; Koomen, John M.; Lynch, Conor C.

doi:10.1038/onc.2017.70

Cited by 11 publications

(8 citation statements)

References 55 publications

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“…Thus, Notch3 is likely operating on the bone tumor microenvironment through at least one other mechanism. MMP-3 is known to promote the cleavage of PTHrP produced by cancer cells, which stimulates osteoblast migration and mineralization in vitro but lacks the osteolytic function associated with full length PTHrP (32). PTHrP also promotes osteoblast proliferation (33).…”

Section: Discussionmentioning

confidence: 99%

Notch3 promotes prostate cancer-induced bone lesion development via MMP-3

et al. 2019

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Prostate cancer metastases primarily localize in the bone where they induce a unique osteoblastic response. Elevated Notch activity is associated with high-grade disease and metastasis. To address how Notch affects prostate cancer bone lesions, we manipulated Notch expression in mouse tibia xenografts and monitored tumor growth, lesion phenotype, and the bone microenvironment. Prostate cancer cell lines that induce mixed osteoblastic lesions in bone expressed 5-6 times more Notch3, than tumor cells that produce osteolytic lesions. Expression of active Notch3 (NICD3) in osteolytic tumors reduced osteolytic lesion area and enhanced osteoblastogenesis, while loss of Notch3 in osteoblastic tumors enhanced osteolytic lesion area and decreased osteoblastogensis. This was accompanied by a respective decrease and increase in the number of active osteoclasts and osteoblasts at the tumor-bone interface, without any effect on tumor proliferation. Conditioned medium from NICD3-expressing cells enhanced osteoblast differentiation and proliferation in vitro, while simultaneously inhibiting osteoclastogenesis. MMP-3 was specifically elevated and secreted by NICD3-expressing tumors, and inhibition of MMP-3 rescued the NICD3-induced osteoblastic phenotypes. Clinical osteoblastic bone metastasis samples had higher levels of Notch3 and MMP-3 compared to patient matched visceral metastases or osteolytic metastasis samples. We identified a Notch3-MMP-3 axis in human prostate cancer bone metastases that contributes to osteoblastic lesion formation by blocking osteoclast differentiation, while also contributing to osteoblastogenesis. These studies define a new role for Notch3 in manipulating the tumor microenvironment in bone metastases. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Section: Discussionmentioning

confidence: 99%

Notch3 promotes prostate cancer-induced bone lesion development via MMP-3

et al. 2019

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“…We further found that this osteolytic suppression is MMP3-dependent. MMP-3 is known to promote the cleavage of PTHrP produced by cancer cells, which stimulates osteoblast migration and mineralization in vitro but lacks the osteolytic function associated with full length PTHrP (39). PTHrP also promotes osteoblast proliferation (40).…”

Section: Discussionmentioning

confidence: 99%

Notch3 Promotes Prostate Cancer-Induced Bone Lesion Development via MMP-3

Ganguly

Hostetter

Tang

et al. 2018

Preprint

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27Prostate cancer metastases primarily localize in the bone where they induce a unique 28 osteoblastic response. Elevated Notch activity is associated with high-grade disease and 29 metastasis. To address how Notch affects prostate cancer bone lesions, we manipulated Notch 30 expression in mouse tibia xenografts and monitored tumor growth, lesion phenotype, and the 31 bone microenvironment. Prostate cancer cell lines that induce mixed osteoblastic lesions in 32 bone expressed 5-6 times more Notch3, than tumor cells that produce osteolytic lesions. 33 Expression of active Notch3 (NICD3) in osteolytic tumors reduced osteolytic lesion area and 34 enhanced osteoblastogenesis, while loss of Notch3 in osteoblastic tumors enhanced osteolytic 35 lesion area and decreased osteoblastogensis. This was accompanied by a respective decrease 36 and increase in the number of active osteoclasts and osteoblasts at the tumor-bone interface, 37 without any effect on tumor proliferation. Conditioned medium from NICD3-expressing cells 38 enhanced osteoblast differentiation and proliferation in vitro, while simultaneously inhibiting 39 osteoclastogenesis. MMP-3 was specifically elevated and secreted by NICD3-expressing 40 tumors, and inhibition of MMP-3 rescued the NICD3-induced osteoblastic phenotypes. Clinical 41 osteoblastic bone metastasis samples had higher levels of Notch3 and MMP-3 compared to 42 patient matched visceral metastases or osteolytic metastasis samples. We identified a Notch3-43 MMP-3 axis in human prostate cancer bone metastases that contributes to osteoblastic lesion 44 formation by blocking osteoclast differentiation, while also contributing to osteoblastogenesis.45 These studies define a new role for Notch3 in manipulating the tumor microenvironment in bone 46 metastases. 47 48 49 50 51 52Death from prostate cancer is primarily due to metastasis (1, 2). Prostate cancer 54 invariably metastasizes to the bone and forms osteoblastic (bone-forming) lesions. Such 55 lesions cause severe bone pain, fractures, bone deformity, hypercalcemia, and immunological 56 complications (1, 3). Even though prostate cancer metastasis is typically osteoblastic, markers 57 of bone turnover indicate that underlying osteolytic events are also involved (4, 5). Death from 58 metastatic bone disease is due in part to the lack of effective therapy, the development of which 59 requires knowing the mechanisms that control osteoblastic versus osteolytic phenotypes. 60 Bone is constantly remodeling during an individual's lifetime. Remodeling depends on 61 two cells types, osteoblasts and osteoclasts, which work in harmony to maintain normal bone. 62 Osteoblasts, derived from mesenchymal stem cells, make new bone. Osteoclasts, derived from 63 monocytes, degrade bone. During osteoblastic metastasis, the bone remodeling balance favors 64 bone formation, i.e. osteoblastogenesis (1, 6). 65 Notch, best known for its role in development and differentiation, is also involved in 66 cancer progression and metastasis. There are four single-pass transmembr...

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“…In skeletal malignancies, for example, MMPs have been shown to process many of the factors that drive cancer-bone interactions, including TGF-β, RANKL, and insulin growth factor (IGF) [135,136,137]. PTHrP has also been identified as a novel substrate of MMP-2, -3, -7, -9, and -13, which predominantly generate PTHrP1–17, 18–26, and 27–36 amino acid products [62]. Notably, the novel PTHrP1–17 product retains the ability to signal through PTH1R whereby it induces the osteogenic activities of full length PTHrP1–36, but it does not impact RANKL and osteoclast formation in vivo, even when dosed continuously.…”

Section: Proteolytic Control Of Pthrp Functionmentioning

confidence: 99%

Proteolytic Regulation of Parathyroid Hormone-Related Protein: Functional Implications for Skeletal Malignancy

Frieling

Lynch

2019

IJMS

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Parathyroid hormone-related protein (PTHrP), with isoforms ranging from 139 to 173 amino acids, has long been implicated in the development and regulation of multiple tissues, including that of the skeleton, via paracrine and autocrine signaling. PTHrP is also known as a potent mediator of cancer-induced bone disease, contributing to a vicious cycle between tumor cells and the bone microenvironment that drives the formation and progression of metastatic lesions. The abundance of roles ascribed to PTHrP have largely been attributed to the N-terminal 1–36 amino acid region, however, activities for mid-region and C-terminal products as well as additional shorter N-terminal species have also been described. Studies of the protein sequence have indicated that PTHrP is susceptible to post-translational proteolytic cleavage by multiple classes of proteases with emerging evidence pointing to novel functional roles for these PTHrP products in regulating cell behavior in homeostatic and pathological contexts. As a consequence, PTHrP products are also being explored as potential biomarkers of disease. Taken together, our enhanced understanding of the post-translational regulation of PTHrP bioactivity could assist in developing new therapeutic approaches that can effectively treat skeletal malignancies.

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Matrix metalloproteinase processing of PTHrP yields a selective regulator of osteogenesis, PTHrP1–17

Cited by 11 publications

References 55 publications

Notch3 promotes prostate cancer-induced bone lesion development via MMP-3

Notch3 promotes prostate cancer-induced bone lesion development via MMP-3

Notch3 Promotes Prostate Cancer-Induced Bone Lesion Development via MMP-3

Proteolytic Regulation of Parathyroid Hormone-Related Protein: Functional Implications for Skeletal Malignancy

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