Circulating Osteogenic Precursor Cells in Heterotopic Bone Formation

Abstract

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 pre-osseous fibroproliferative lesions in patients with fibrodysplasia ossificans progressiva (FOP) and nucleate heterotopic ossification (HO) in a murine in vivo implantation assay. Blood samples from FOP patients 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 prior to 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.

Circulating osteogenic cells: Implications for injury, repair, and regeneration

“…There is increasing evidence that COP cells participate in HO after hip arthroplasty, in end-stage aortic valvular disease, and in a genetic syndrome of extraskeletal bone formation. (16,62,63) Animal models of ectopic bone formation also support the notion of COP cell involvement in lesion formation. (12,13,16) In a rare genetic disorder of HO, FOP, patients with active episodes of extraskeletal bone formation have higher numbers of clonally derived COP cell colonies than patients with stable disease or unaffected individuals, and these COP cells are present in early fibroproliferative lesions.…”

Botulinum Toxin-induced Muscle Paralysis Inhibits Heterotopic Bone Formation

“…Given the known mechanism of action of BTxA (inhibition of neurotransmitter release), we therefore speculated that the blockade of neuromuscular signaling by BTxA inhibits neuromuscular interactions integral to the osteogenic response elicited by musculoskeletal trauma. Furthermore, because fracture healing and HO share common initiating events (including inflammation and BMP signaling) [17,27,30,32], we also speculated that BTxA-induced muscle paralysis would prevent the formation of heterotopic bone. However, interpreting the precise mechanism by which muscle paralysis inhibits osteogenesis in the rat fracture model is confounded by the heterogeneity of the tissue response, soft tissue injury, and modified gait kinematics, all of which can alter the observed cellular responses.…”

CD34-negative mesenchymal stem-like cells may act as the cellular origin of human aortic valve calcification

“…Furthermore, two recent studies reported that aortic valve calcification is associated with ectopic ossification induced by various bone marrow-derived circulating osteogenic progenitor (COP) cells, such as type I collagen/CD45-positive and/or osteocalcin/CD45-positive cells [12,13]. However, whether these progenitor cells that reside in the aortic valve trigger valve calcification has yet to be confirmed.…”