Gregory A. Clines

Basic Mechanisms Responsible for Osteolytic and Osteoblastic Bone Metastases

Certain solid tumors metastasize to bone and cause osteolysis and abnormal new bone formation. The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases.

Molecular mechanisms and treatment of bone metastasis.

The metastasis of cancer cells to bone alters bone architecture and mineral homeostasis. As described by the seed and soil hypothesis, bone represents a fertile ground for cancer cells to flourish. A vicious cycle of reciprocal bone-cancer cellular signals occurs with osteolytic (bone-resorbing) metastases, and a similar mechanism likely modulates osteoblastic (bone-forming) metastatic lesions as well. The development of targeted therapies either to block initial cancer cell chemotaxis, invasion and adhesion or to break the vicious cycle is dependent on a more complete understanding of bone metastases. Although bisphosphonates delay progression of skeletal metastases, it is clear that more-effective therapies are needed. Cancer-associated bone morbidity remains a major public health problem, and to improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review details scientific advances in this area.

Mechanisms and treatment of hypercalcemia of malignancy.

Purpose of review Hypercalcemia of malignancy is a common paraneoplastic syndrome and a frequent complication of advanced breast and lung cancer, and multiple myeloma. The development of this malignancy complication often purports a poor prognosis. Thorough evaluation to establish the cause of hypercalcemia is essential because some patients may actually have undiagnosed primary hyperparathyroidism. Recent findings Production of humoral factors by the primary tumor, collectively known as humoral hypercalcemia of malignancy (HHM), is the mechanism responsible for 80% of cases. The vast majority of HHM is caused by tumor-produced parathyroid hormone-related protein followed by infrequent tumor production of 1,25-dihydroxyvitamin D and parathyroid hormone. The remaining 20% of cases are caused by bone metastasis with consequent bone osteolysis and release of skeletal calcium. Key therapies are saline hydration to promote calciuresis and bisphosphonates to reduce pathologic osteoclastic bone resorption. Calcitonin and glucocorticoids, especially in 1,25-dihydroxyvitamin D-mediated HHM, also have calcium-lowering effects. Summary Recent discoveries on mechanisms of malignancy-associated hypercalcemia highlight the critical role of the osteoclast. Bisphosphonates and other novel therapies being evaluated in clinical trial target this bone-resorbing cell type and provide effective and durable serum calcium reduction.

The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone

Transforming growth factor-β (TGF-β) regulates the expression of genes supporting breast cancer cells in bone, but little is known about prostate cancer bone metastases and TGF-β. Our study reveals that the TGFBR1 inhibitor SD208 effectively reduces prostate cancer bone metastases. TGF-β upregulates in prostate cancer cells a set of genes associated with cancer aggressiveness and bone metastases, and the most upregulated gene was PMEPA1. In patients, PMEPA1 expression decreased in metastatic prostate cancer and low Pmepa1 correlated with decreased metastasis-free survival. Only membrane-anchored isoforms of PMEPA1 interacted with R-SMADs and ubiquitin ligases, blocking TGF-β signaling independently of the proteasome. Interrupting this negative feedback loop by PMEPA1 knockdown increased prometastatic gene expression and bone metastases in a mouse prostate cancer model.

Prospects for osteoprogenitor stem cells in fracture repair and osteoporosis.

Purpose of reviewBone regeneration and fracture repair are the complex processes of mesenchymal stem cell invasion, chondrogenesis, osteogenesis and angiogenesis. The coordinated actions of these principal processes result in the reconstruction of a normal bone and restoration of a structural unit. However, these normal bone regenerative mechanisms breakdown during fracture repair failure and postmenopausal osteoporosis. Recent findingsRecent discoveries of circulating multipotent stem cells with mixed characteristics of endothelial cell and osteogenic capacity have raised interest in new and potentially breakthrough therapies for fracture and pathologic bone loss. The cooperative actions of other mesenchymal stem cell lineage such as adipocytes and processes such as angiogenesis in bone repair could also serve as novel therapeutic targets. Recent data suggest that anabolic parathyroid hormone therapy, already approved for the treatment of osteoporosis, may recruit osteoprogenitor cells and also have a role in fracture repair. SummaryThe present review will highlight recent information on stem cells and bone repair and examine potential avenues for future research.

Cystic fibrosis-related bone disease: insights into a growing problem.

Purpose of reviewThis review will describe the clinical significance, pathogenesis and treatment of cystic fibrosis related bone disease (CFBD). Recent findingsCFBD continues to increase as the life expectancy of individuals with cystic fibrosis increases. According to clinical guidelines, individuals with cystic fibrosis should be initially screened at the age of 18 years via dual-energy x-ray absorptiometry, if not done so previously. The underlying pathogenesis of CFBD appears to be multifactorial, but increasing data imply a direct impact by the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR deficiency and/or dysfunction impair osteoblast activity and differentiation, and indirectly promote osteoclast formation. Unfortunately, once diagnosed with CFBD, few cystic fibrosis tested medical therapies exist. SummaryCFBD is an increasingly recognized complication that has a significant impact on the overall health of the individual. Recommendations to identify patients with cystic fibrosis who are at risk for fracture using dual-energy x-ray absorptiometry have been established. Therapeutic agents directly studied in patients with cystic fibrosis are limited to bisphosphonates, although other potential treatment agents exist. Finally, an improved understanding of the pathologic mechanisms will aid in the study and development of therapies.

Regulation of Postnatal Trabecular Bone Formation by the Osteoblast Endothelin A Receptor

Endothelin‐1 (ET‐1) is a potent vasoconstrictor that also stimulates cells in the osteoblast lineage by binding to the endothelin A receptor (ETAR). ET‐1 ligand is widely secreted, particularly by the vasculature. However, the contributions of ETAR signaling to adult bone homeostasis have not been defined. ETAR was inactivated in osteoblasts by crossing ETAR‐floxed and osteocalcin‐Cre mice. Histomorphometric analyses were performed on 4‐, 8‐, and 12‐week‐old osteoblast‐targeted ETAR knockout (KO) and wild‐type (WT) male and female mice. Tibial trabecular bone volume was significantly lower from 12 weeks in KO versus WT mice in both males and females. Bone‐formation rate, osteoblast density, and in vitro osteoblast differentiation were reduced by targeted inactivation of ETAR. A separate longitudinal analysis was performed between 8 and 64 weeks to examine the effect of aging and castration on bone metabolism in ETAR KO mice. Hypogonadism did not change the rate of bone accrual in WT or KO females. However, eugonadal KO males had a significantly larger increase in tibial and femoral bone acquisition than WT mice. Male mice castrated at 8 weeks of age showed the reverse: KO mice had reduced rates of tibial and femoral BMD acquisition compared with WT mice. In vitro, ET‐1 increased osteoblast proliferation, survival, and differentiation. Dihydrotestosterone also increased osteoblast differentiation using a mechanism distinct from the actions of ET‐1. These results demonstrate that endothelin signaling in osteoblasts is an important regulator of postnatal trabecular bone remodeling and a modulator of androgen effects on bone.

Corrigendum to: Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research (J Bone Miner Res, (2016), 31, (16-35), 10.1002/jbmr.2708)

1. Adler, R. A., El-Hajj Fuleihan, G., Bauer, D. C., Camacho, P.M., Clarke, B. L., Clines, G. A., Compston, J. E., Drake, M. T., Edwards, B. J., Favus, M. J., Greenspan, S. L., McKinney, R., Pignolo, R. J. and Sellmeyer, D. E. (2016), Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res, 31: 16–35. doi: 10.1002/jbmr.2708 CORRIGENDUM JBMR

Local effects of malignancy on bone

Purpose of reviewSkeletal-related complications occur commonly in many solid tumors including breast, prostate and lung cancer as well as multiple myeloma. In addition, malignancies and their associated treatment may result in bone loss or osteoporosis. This review will focus solely on recent data associated with metastatic bone disease with a focus on breast cancer, prostate cancer and multiple myeloma. Bone loss or osteoporosis associated with cancer will be covered in a separate article in this issue. Recent findingsRecent progress in understanding the pathophysiology of bone metastases has pointed to several novel pathways: transforming growth factor β; receptor activator of nuclear factor β ligand and osteoprotegerin; and Wnt signaling pathways and associated factors such as dickkopf-1 and endothelin-1. SummaryThe identification of new pathways is important in metastatic bone disease from cancer and has allowed for the development of novel therapeutics aimed at preventing the devastating complications of bone metastases. Bisphosphonates remain the predominant therapy in use for the treatment and prevention of skeletal-related adverse effects from cancer.

Dural Cells Release Factors Which Promote Cancer Cell Malignancy and Induce Immunosuppressive Markers in Bone Marrow Myeloid Cells

BACKGROUNDnThirty per cent of cancer patients develop spine metastases with a substantial number leading to spinal cord compression and neurological deficits. Many demonstrate a propensity toward metastasis to the posterior third of the vertebral body. The dura, the outer layer of the meninges, lies in intimate contact with the posterior border of the vertebral body and has been shown to influence adjacent bone. The effects of the dura on bone marrow and cancer cells have not been examined. Understanding the biology of spinal metastasis will provide insights into mechanisms of cancer growth and allow for new treatment strategies.nnnOBJECTIVEnTo examine the extent to which dura influences bone marrow/tumor cell metastatic characteristics.nnnMETHODSnDura conditioned media (DCM) from primary dura was examined for the ability to stimulate tumor cell proliferation/invasion and to alter bone marrow cell populations. RNA sequencing of dural fibroblasts was performed to examine expression of cytokines and growth factors.nnnRESULTSnDCM induced a significant increase in invasion and proliferation of multiple tumor cell lines, and of patient-derived primary spinal metastatic cells. DCM also increased the proliferation of bone marrow myeloid cells, inducing expression of immunosuppressive markers. RNA sequencing of dural fibroblasts demonstrated abundant expression of cytokines and growth factors involved in cancer/immune pathways.nnnCONCLUSIONnFactors released by primary dural cells induce proliferation of tumor cells and alter bone marrow to create a fertile environment for tumor growth. The dura therefore may play an important role in the increased incidence of metastases to adjacent bone.