Maja Hinge

Early reversal cells in adult human bone remodeling: osteoblastic nature, catabolic functions and interactions with osteoclasts

The mechanism coupling bone resorption and formation is a burning question that remains incompletely answered through the current investigations on osteoclasts and osteoblasts. An attractive hypothesis is that the reversal cells are likely mediators of this coupling. Their nature is a big matter of debate. The present study performed on human cancellous bone is the first one combining in situ hybridization and immunohistochemistry to demonstrate their osteoblastic nature. It shows that the Runx2 and CD56 immunoreactive reversal cells appear to take up TRAcP released by neighboring osteoclasts. Earlier preclinical studies indicate that reversal cells degrade the organic matrix left behind by the osteoclasts and that this degradation is crucial for the initiation of the subsequent bone formation. To our knowledge, this study is the first addressing these catabolic activities in adult human bone through electron microscopy and analysis of molecular markers. Periosteoclastic reversal cells show direct contacts with the osteoclasts and with the demineralized resorption debris. These early reversal cells show (1) ¾-collagen fragments typically generated by extracellular collagenases of the MMP family, (2) MMP-13 (collagenase-3) and (3) the endocytic collagen receptor uPARAP/Endo180. The prevalence of these markers was lower in the later reversal cells, which are located near the osteoid surfaces and morphologically resemble mature bone-forming osteoblasts. In conclusion, this study demonstrates that reversal cells colonizing bone surfaces right after resorption are osteoblast-lineage cells, and extends to adult human bone remodeling their role in rendering eroded surfaces osteogenic.

Whole-body computed tomography versus conventional skeletal survey in patients with multiple myeloma: A study of the International Myeloma Working Group

For decades, conventional skeletal survey (CSS) has been the standard imaging technique for multiple myeloma (MM). However, recently whole-body computed tomography (WBCT) has been implemented into the diagnostic criteria of MM. This analysis compares sensitivity and prognostic significance of WBCT and CSS in patients with smoldering MM (SMM) and MM. Fifty-four of 212 patients (25.5%) had a negative CSS and a positive WBCT for osteolytic lesions (P<0.0001). Of 66 patients with SMM based on CSS, 12 (22.2%) had osteolytic lesions on WBCT. In comparison, WBCT failed to detect some bone destructions in the appendicular skeleton possibly due to limitations of the field of view. Presence of lytic bone lesions in WBCT was of borderline prognostic significance (P=0.051) for SMM patients, with a median time to progression of 38 versus 82 months for those without bone destructions. In conclusion, WBCT identifies significantly more sites of bone destruction than CSS. More than 20% of patients with SMM according to CSS have in fact active MM detectable with WBCT. On the basis of this and other studies, WBCT (either computed tomography (CT) alone or as part of a positron emission tomography-CT protocol) should be considered the current standard for the detection of osteolytic lesions in MM.

Bone healing in multiple myeloma: A prospective evaluation of the impact of first-line anti-myeloma treatment.

Myeloma cells disturb a normally balanced bone remodeling process. This imbalance of bone metabolism may cause osteopenic bones, focal osteolytic lesions and clinical symptoms. The excess bone resorption resulting in osteolytic lesions has traditionally been perceived as irreversible. We

Patient pools and the use of "patient means" are valuable tools in quality control illustrated by a bone-specific alkaline phosphatase assay.

Abstract Background: Quality control (QC) is an essential part of clinical biochemistry to ensure that laboratory test results are reliable and correct. Those tests without a defined reference method constitute a special challenge, as is the case with bone-specific alkaline phosphatase (BAP). Methods and Results: The present study reports an example where a shift in a BAP assay was detected by use of a patient pool and supported by a retrospective calculation of “patient mean”, while the external QC and specific assay control material were unaffected by the shift. Conclusions: Patient pools and the use of patient means remain a useful and inexpensive procedure for internal QC.

Baseline bone involvement in multiple myeloma - a prospective comparison of conventional X-ray, low-dose computed tomography, and 18flourodeoxyglucose positron emission tomography in previously untreated patients

Examination of bone lesions is a compulsory part of baseline assessments in patients with multiple myeloma (MM). Low-dose computed tomography (CT) scan has recently been recommended as a replacement of conventional X-ray for the diagnosis of osteolytic lesions by the European Myeloma Network.[1][1]

Bone Disease in Multiple Myeloma

Osteolytic bone disease in multiple myeloma (MM) is a common event. Already at diagnosis, approximately eighty percent of patients present with abnormal bone structure [1;2]. During disease progression a large proportion of patients will develop ostelytic lesions [3]. MM bone disease not only results in a reduced quality of life due to pain, pathological fractures, or symptomatic hypercalcaemia [4]; but may also be the deciding factor that determines if a patient requires anti-myeloma treatment or if a watch and wait strategy can be applied [5]. In this chapter we will discuss the normal bone remodelling process, and how it is affected in MM. During the last decades, increased knowledge about bone pathophysiology in general has led to an improved understanding of MM bone disease. The description of the receptor activator of nuclear factor kappa B (RANK) and its ligand in the nineties was one of the most significant steps. We will also address how biochemical markers may be used to monitor the velocity of the different processes in bone remodelling. The next part of the chapter will be dedicated to the treatment of MM bone disease. For many years, bisphosphonates have been a cornerstone in the treatment of MM bone disease and despite the occurrence of osteonecrosis of the jaw that was first report‐ ed as a result of the of bisphosphonate treatment in the early part of this century, these agents remain the most important components of treatment for MM bone disease. Lastly, we will discuss how various anti-myeloma treatments may influence bone turnover. During the last decade a number of novel drugs have been approved for the treatment of MM and especially proteasome inhibitors seems to have a positive effect on MM bone disease besides their anti-myleoma effect.

High‐dose therapy improves the bone remodelling compartment canopy coverage and bone formation in multiple myeloma

Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling. Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high‐dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first‐line treatment with high‐dose melphalan followed by autologous stem cell transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed that a good response to anti‐myeloma treatment increased the extent of formative bone surfaces with canopy, and reduced the extent of eroded surfaces without canopy, reverting the uncoupled bone remodelling, while improving canopy coverage. The association between improved coupling and the canopy coverage supports the notion that canopies are critical for the coupling of bone formation to resorption. Furthermore, this study supports the observation that systemic bone disease in MM can be reversed in MM patients responding to anti‐myeloma treatment.

Early reversal cells: Osteoblastic nature, catabolic function and interaction with osteoclasts

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