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Circulating osteogenic progenitor (COP) cells are a population of cells in the peripheral blood with the capacity for bone formation, as well as broader differentiation into mesoderm-like cells in vitro. Although some of their biological characteristics are documented in vitro, their role in diseases of the musculoskeletal system remains yet to be fully evaluated. In this review, we provide an overview of the role of COP cells in a number of physiological and pathological conditions, as well as identify areas for future research. In addition, we suggest possible areas for clinical utilization in the management of musculoskeletal diseases. © 2020 American Society for Bone and Mineral Research (ASBMR)., (© 2020 American Society for Bone and Mineral Research (ASBMR).)

Non-hereditary heterotopic ossification (NHHO) may occur after musculoskeletal trauma, central nervous system (CNS) injury, or surgery. We previously described circulating osteogenic precursor (COP) cells as a bone marrow-derived type 1 collagen + CD45 + subpopulation of mononuclear adherent cells that are able of producing extraskeletal ossification in a murine in vivo implantation assay. In the current study, we performed a tissue analysis of COP cells in NHHO secondary to defined conditions, including traumatic brain injury, spinal cord injury, cerebrovascular accident, trauma without neurologic injury, and joint arthroplasty. All bone specimens revealed the presence of COP cells at 2-14 cells per high power field. COP cells were localized to early fibroproliferative and neovascular lesions of NHHO with evidence for their circulatory status supported by their presence near blood vessels in examined lesions. This study provides the first systematic evaluation of COP cells as a contributory histopathological finding associated with multiple forms of NHHO. These data support that circulating, hematopoietic-derived cells with osteogenic potential can seed inflammatory sites, such as those subject to soft tissue injury, and due to their migratory nature, may likely be involved in seeding sites distant to CNS injury., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The formation of bone outside the endogenous skeleton is a significant clinical event, rendering affected individuals with immobility and a diminished quality of life. This bone, termed heterotopic ossification (HO), can appear in patients following invasive surgeries and traumatic injuries, as well as progressively manifest in several congenital disorders. A unifying feature of both genetic and nongenetic episodes of HO is immune system involvement at the early stages of disease. Activation of the immune system sets the stage for the downstream anabolic events that eventually result in ectopic bone formation, rendering the immune system a particularly appealing site of early therapeutic intervention for optimal management of disease. In this review, we will discuss the immunological contributions to HO disorders, with specific focus on contributing cell types, signaling pathways, relevant in vivo animal models, and potential therapeutic targets.

Unlabelled: Bone tissue adapts to its functional environment by optimizing its morphology for mechanical demand. Among the mechanosensitive cells that recognize and respond to forces in the skeleton are osteocytes, osteoblasts, and mesenchymal progenitor cells (MPCs). Therefore, the ability to use mechanical signals to improve bone health through exercise and devices that deliver mechanical signals is an attractive approach to age-related bone loss; however, the extracellular or circulating mediators of such signals are largely unknown. Using SDS-PAGE separation of proteins secreted by MPCs in response to low-magnitude mechanical signals and in-gel trypsin digestion followed by HPLC and mass spectroscopy, we identified secreted proteins up-regulated by vibratory stimulation. We exploited a cell senescence-associated secretory phenotype screen and reasoned that a subset of vibration-induced proteins with diminished secretion by senescent MPCs will have the capacity to promote bone formation in vivo. We identified one such vibration-induced bone-enhancing (vibe) gene as R-spondin 1, a Wnt pathway modulator, and demonstrated that it has the capacity to promote bone formation in three mouse models of age-related bone loss. By virtue of their secretory status, some vibe proteins may be candidates for pre-clinical development as anabolic agents for the treatment of osteoporosis., Key Message: Mesenchymal stem cells respond to low magnitude mechanical signals (vibration). R-Spondin 1 is upregulated by mechanical signals and secreted. R-Spondin 1 promotes bone formation in three mouse models of osteoporosis.

Objective: Approximately 13% of aortic valves removed from patients with end-stage aortic valve disease contain heterotopic ossification (HO). Recently, we identified a novel population of circulating osteogenic precursor (COP) cells that are derived from bone marrow and have the capability to form bone. These cells are identified by coexpression of the osteogenic marker type 1 collagen or osteoclacin and the hematopoietic marker CD45. We tested the hypothesis that these cells may contribute to heart valve stenosis., Methods and Results: Quantification of CD45(+) osteoclacin(+) COP cells by flow cytometry showed that they represent up to 1.1% of mononuclear cells. Clonally derived COP cells produce bone morphogenetic proteins 2 and 4 by immunohistochemical analysis. We reviewed 105 cases of end-stage aortic valvular disease and confirmed HO in 13 archived specimens. Using immunohistochemistry, we identified COP cells by coexpression of CD45 and type 1 collagen. There was a statistically significant association between the presence of COP cells and early HO lesions. COP cells were negligible in regions of unaffected valve leaflets (no HO) from the same individuals., Conclusions: This study provides the first evidence that osteogenic cells in the blood home to sites of vascular injury and are associated with HO formation in heart valves.

The aim of this review is to provide a critical reading of recent literature pertaining to the presence of circulating, fluid-phase osteoblastic cells and their possible contribution to bone formation. We have termed this group of cells collectively as circulating osteogenic precursor (COP) cells. We present evidence for their existence, methods used for their isolation and identification, possible physiological and pathophysiological roles, cellular origins, and possible mechanisms for their migration to target tissues., (Copyright © 2011 American Society for Bone and Mineral Research.)

Circulating osteogenic precursor (COP) cells are blood-borne cells that express a variety of osteoblastic markers and are able to form bone in vivo. Strong evidence suggests that COP cells are derived from bone marrow and are of hematopoietic origin. The study of COP cells has been limited by several factors, including the difficulty in establishing long-term cultures and lack of a standardized protocol for their isolation and identification. However, experimental evidence supports that COP cells seed sites of injury and inflammation in response to homing signals and are involved in processes of pubertal growth, fracture, and diverse conditions of heterotopic bone formation. The role of COP cells in physiologic and pathophysiologic conditions of de novo bone formation suggests that they may serve as future targets for diagnostic measurements and therapeutic interventions.

Cells with osteogenic potential can be found in a variety of tissues. Here we show that circulating osteogenic precursor (COP) cells, a bone marrow-derived type I collagen+/CD45+ subpopulation of mononuclear adherent cells, are present in early preosseous fibroproliferative lesions in patients with fibrodysplasia ossificans progressiva (FOP) and nucleate heterotopic ossification (HO) in a murine in vivo implantation assay. Blood samples from patients with FOP with active episodes of HO contain significantly higher numbers of clonally derived COP cell colonies than patients with stable disease or unaffected individuals. The highest level of COP cells was found in a patient just before the clinical onset of an HO exacerbation. Our studies show that even COP cells derived from an unaffected individual can contribute to HO in genetically susceptible host tissue. The possibility that circulating, hematopoietic-derived cells with osteogenic potential can seed inflammatory sites has tremendous implications and, to our knowledge, represents the first example of their involvement in clinical HO. Thus, bone formation is not limited to cells of the mesenchymal lineage, and circulating cells of hematopoietic origin can also serve as osteogenic precursors at remote sites of tissue inflammation.

Matrix-producing osteoblasts and bone-resorbing osteoclasts maintain bone homeostasis. Osteoclasts are multinucleated, giant cells of hematopoietic origin formed by the fusion of mononuclear pre-osteoclasts derived from myeloid cells. Fusion-mediated giant cell formation is critical for osteoclast maturation; without it, bone resorption is inefficient. To understand how osteoclasts differ from other myeloid lineage cells, we previously compared global mRNA expression patterns in these cells and identified genes of unknown function predominantly expressed in osteoclasts, one of which is the d2 isoform of vacuolar (H(+)) ATPase (v-ATPase) V(0) domain (Atp6v0d2). Here we show that inactivation of Atp6v0d2 in mice results in markedly increased bone mass due to defective osteoclasts and enhanced bone formation. Atp6v0d2 deficiency did not affect differentiation or the v-ATPase activity of osteoclasts. Rather, Atp6v0d2 was required for efficient pre-osteoclast fusion. Increased bone formation was probably due to osteoblast-extrinsic factors, as Atp6v02 was not expressed in osteoblasts and their differentiation ex vivo was not altered in the absence of Atp6v02. Our results identify Atp6v0d2 as a regulator of osteoclast fusion and bone formation, and provide genetic data showing that it is possible to simultaneously inhibit osteoclast maturation and stimulate bone formation by therapeutically targeting the function of a single gene.