Targeting the BMP Pathway in Prostate Cancer Induced Bone Disease

Straign, Desiree; Ihle, Claire L.; Provera, Meredith D.; Owens, Philip

doi:10.3389/fendo.2021.769316

Cited by 10 publications

(8 citation statements)

References 44 publications

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“…These include bone morphogenic proteins (BMPs), osteopontin, and the Wnt/β catenin pathway, each of which stimulates downstream Runt‐domain transcription factor signaling and aberrant osteoblast activation. ( 27 , 28 ) Overactive bone formation enhances tumor growth and further compromises the bone marrow compartment. Preclinical models have demonstrated that inhibition of BMP signaling in particular can limit the osteoblastic response and, to some extent, indirectly suppress tumor growth ( 27 ) ; however, to date these approaches have not translated to the clinic.…”

Section: Discussionmentioning

confidence: 99%

Increased Bone Formation and Accelerated Bone Mass Accrual in a Man Presenting with Diffuse Osteosclerosis/High Bone Mass Phenotype and Adenocarcinoma of Unknown Primary

et al. 2023

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A 71‐year‐old man was referred for evaluation of incidental generalized osteosclerosis. He was found to have a high bone mass (HBM) with an elevated lumbar spine bone mineral density (BMD) Z‐score of +5.3. Over an 18‐month period, his lumbar spine BMD measured by dual energy X‐ray absorptiometry (DXA) had increased by +64% from 1.09 to 1.79 g/cm2 and femoral neck by +21% from 0.83 to 1.01 g/cm2. Biochemical markers of bone turnover were markedly increased (serum propeptide of type 1 collagen and urine telopeptides greater than 10‐times normal). The high bone formation and increased skeletal calcium acquisition resulted in profound hypocalcemia (low serum calcium 1.88 mmol/L) and hypocalciuria (low urinary calcium <0.2 mmol/day). Positron emission tomography (PET) with 2‐deoxy‐2‐[fluorine‐18] fluoro‐D‐glucose (FDG) confirmed diffuse osteosclerosis without focal areas of abnormal FDG uptake in the skeleton or elsewhere to suggest either an underlying primary malignancy or metastatic disease. Bone biopsy showed markedly sclerotic woven and lamellar bone. The marrow space was devoid of typical bone cells and adipocytes and instead was filled by fibromyxoid stroma, infiltrated by small clusters of tumor cells. Bone histomorphometry and micro–computed tomography demonstrated an elevated trabecular bone volume and trabecular plate thickness. The bone disorder in this case is unique and raises the possibility of a new yet undefined novel anabolic paracrine factor (or factors) secreted by an adenocarcinoma of unknown primary that resulted in dramatic increases in BMD, HBM, and radiological osteosclerosis. The differential diagnosis and potential mechanisms responsible for the HBM are discussed. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Increased Bone Formation and Accelerated Bone Mass Accrual in a Man Presenting with Diffuse Osteosclerosis/High Bone Mass Phenotype and Adenocarcinoma of Unknown Primary

et al. 2023

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“…BMPs have recently been shown to have expanded roles in osteoclasts and bone resorption which can be instrumental in the heightened lytic vicious cycle of tumor induced bone disease 49,50 . BMP inhibition of lytic‐like lesions may be more preferential than blastic‐like lesions if those lesions are driven by BMP‐directed osteoclastogenesis as compared to TGFβ‐driven sclerosis 51 . It has also been demonstrated in multiple myeloma that BMP inhibition of osteolytic lesions improved bone quality through combined lineages of bone matrix producing cells 52 .…”

Section: Discussionmentioning

confidence: 99%

“… 49 , 50 BMP inhibition of lytic‐like lesions may be more preferential than blastic‐like lesions if those lesions are driven by BMP‐directed osteoclastogenesis as compared to TGFβ‐driven sclerosis. 51 It has also been demonstrated in multiple myeloma that BMP inhibition of osteolytic lesions improved bone quality through combined lineages of bone matrix producing cells. 52 Genetic and pharmacologic loss of function studies for BMPR1a have surprisingly resulted in improvement in bone formation as opposed to expected loss in BMP directed osteogenesis.…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein pathway responses and alterations of osteogenesis in metastatic prostate cancers

et al. 2022

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Background: Prostate cancer is a common cancer in men that annually results in more than 33 000 US deaths. Mortality from prostate cancer is largely from metastatic disease, reflecting on the great strides in the last century of treatments in care for the localized disease. Metastatic castrate resistant prostate cancer (mCRPC) will commonly travel to the bone, creating unique bone pathology that requires nuanced treatments in those sites with surgical, radio and chemotherapeutic interventions.The bone morphogenetic protein (BMP) pathway has been historically studied in the capacity to regulate the osteogenic nature of new bone. New mineralized bone generation is a frequent and common observation in mCRPC and referred to as blastic bone lesions. Less common are bone destructive lesions that are termed lytic.Methods: We queried the cancer genome atlas (TCGA) prostate cancer databases for the expression of the BMP pathway and found that distinct gene expression of the ligands, soluble antagonists, receptors, and intracellular mediators were altered in localized versus metastatic disease. Human prostate cancer cell lines have an innate ability to promote blastic-or lytic-like bone lesions and we hypothesized that inhibiting BMP signaling in these cell lines would result in a distinct change in osteogenesis gene expression with BMP inhibition.Results: We found unique and common changes by comparing these cell lines response and unique BMP pathway alterations. We treated human PCa cell lines with distinct bone pathologic phenotypes with the BMP inhibitor DMH1 and found distinct osteogenesis responses. We analyzed distinct sites of metastatic PCa in the TCGA and found that BMP signaling was selectively altered in commons sites such as lymph node, bone and liver compared to primary tumors.Conclusions: Overall we conclude that BMPs in metastatic prostate cancer are important signals and functional mediators of diverse processes that have potential for individualized precision oncology in mCRPC.

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“…In myeloma bone disease, inhibition of BMP signaling prevented bone loss by reducing osteoclastogenesis and promoted osteoblast differentiation by reducing the concentration of sclerostin the bone marrow [123]. Pharmacologic inhibition of BMP signaling by small molecule antagonist DMH1 in prostate cancer models of bone metastasis restricted cancer cell colonization to bone in immunodeficient mice; however, in mice with intact immune system, DHM1 had no effect on tumor growth and bone health [124]. Interestingly, numerous studies identified a dual role of BMPs in cancer development with BMPs acting both as tumor promoters or suppressors [125].…”

Section: Growth Factors Mediating Bone Defectsmentioning

confidence: 99%

Muscle and Bone Defects in Metastatic Disease

Pauk

Saito

Hesse

et al. 2022

Curr Osteoporos Rep

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Purpose of Review The present review addresses most recently identified mechanisms implicated in metastasis-induced bone resorption and muscle-wasting syndrome, known as cachexia. Recent Findings Metastatic disease in bone and soft tissues is often associated with skeletal muscle defects. Recent studies have identified a number of secreted molecules and extracellular vesicles that contribute to cancer cell growth and metastasis leading to bone destruction and muscle atrophy. In addition, alterations in muscle microenvironment including dysfunctions in hepatic and mitochondrial metabolism have been implicated in cancer-induced regeneration defect and muscle loss. Moreover, we review novel in vitro and animal models including promising new drug candidates for bone metastases and cancer cachexia. Summary Preservation of bone health could be highly beneficial for maintaining muscle mass and function. Therefore, a better understanding of molecular pathways implicated in bone and muscle crosstalk in metastatic disease may provide new insights and identify new strategies to improve current anticancer therapeutics.

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Targeting the BMP Pathway in Prostate Cancer Induced Bone Disease

Cited by 10 publications

References 44 publications

Increased Bone Formation and Accelerated Bone Mass Accrual in a Man Presenting with Diffuse Osteosclerosis/High Bone Mass Phenotype and Adenocarcinoma of Unknown Primary

Increased Bone Formation and Accelerated Bone Mass Accrual in a Man Presenting with Diffuse Osteosclerosis/High Bone Mass Phenotype and Adenocarcinoma of Unknown Primary

Bone morphogenetic protein pathway responses and alterations of osteogenesis in metastatic prostate cancers

Muscle and Bone Defects in Metastatic Disease

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