Involvement of integrins α₃β₁ and α₅β₁ and glycoprotein IIb in megakaryocyte‐induced osteoblast proliferation

Abstract

As the prevalence of osteoporosis is expected to increase over the next few decades, the development of novel therapeutic strategies to combat this disorder becomes clinically imperative. These efforts draw extensively from an expanding body of knowledge pertaining to the physiologic mechanisms of skeletal homeostasis. To this body of knowledge, we contribute that cells of hematopoietic lineage may play a crucial role in balancing osteoblastic bone formation against osteoclastic resorption. Specifically, our laboratory has previously demonstrated that megakaryocytes (MK) can induce osteoblast (OB) proliferation in vitro, but do so only when direct cell-to-cell contact is permitted. To further investigate the nature of this interaction, we have effectively neutralized several adhesion molecules known to function in the analogous interaction of MKs with another cell-type of mesenchymal origin -the fibroblast (FB). Our findings implicate the involvement of fibronectin/RGD-binding integrins including α 3 β 1 (VLA-3) and α 5 β 1 (VLA-5) as well as glycoprotein IIb (CD41), all of which are known to be expressed on MK membranes. Furthermore, we demonstrate that interleukin (IL)-3 can enhance MK-induced OB activation in vitro, as demonstrated in the MK-FB model system. Taken together, these results suggest that although their physiologic and clinical implications are very different, these two models of hematopoietic-mesenchymal cell activation are mechanistically analogous in several ways. KeywordsMegakaryocytes; Osteoblasts; Integrins; CD41; IL-3 Skeletal fragility has emerged as a major limitation to quality of life as we age. Osteoporosis and the ensuing hip, wrist, and vertebral fractures are significant sources of morbidity and pain among the elderly: such a fracture can be the sentinel event that transforms a relatively healthy, independent senior citizen into a person requiring significant assistance for daily living. This downward spiral is evidenced by a one-year post-hip fracture mortality of 24 percent (National Osteoporosis Foundation). As the prevalence of osteoporosis is expected to increase over the next few decades, the development of novel therapeutic strategies to combat this disorder becomes clinically imperative. These efforts draw extensively from an expanding body of knowledge pertaining to the physiologic mechanisms of skeletal homeostasis. To this body of knowledge, we contribute that cells of hematopoietic lineage may play a crucial role in balancing osteoblastic bone formation against osteoclastic resorption. (Thiede et al., 1994;Kelm et al., 1992;Breton-Gorius et al., 1992;Chenu and Delmas, 1992;Frank et al., 1993;Sipe et al., 2004;Kacena et al., 2004;Ciovacco et al., 2009;Miao et al., 2004;Bord et al., 2005; Ciovacco et al., in press). Simultaneously, MKs may regulate bone resorption by expressing/secreting several factors known to be involved in osteoclastogenesis, and recent studies demonstrate that MKs can inhibit osteoclast (OC) formation in vitro (Ciovacco et al., in press;Bord...

Megakaryocytes Regulate Expression of Pyk2 Isoforms and Caspase-mediated Cleavage of Actin in Osteoblasts

“…We previously reported that OB cell number is significantly increased when OBs are co-cultured with MKs in vitro (1,2,4). In addition, our studies reveal that MKs stimulate OB proliferation in part through direct cell-cell contact and via a mechanism that requires integrin engagement (5). Furthermore, in GATA-1-deficient mice in which MK numbers are increased, bone mineral density is increased (6), and histological evaluation reveals an increase in OB numbers on trabecular surfaces, suggesting that MKs stimulate OB proliferation in vivo.…”

“…MKs are responsible for the production of thrombocytes, which are necessary for blood clotting. Although the mechanism has yet to be fully elucidated, a growing body of evidence also suggests that MKs play a key role in regulating skeletal homeostasis through direct and indirect effects on OBs and osteoclasts (1)(2)(3)(4)(5)(6). We previously reported that OB cell number is significantly increased when OBs are co-cultured with MKs in vitro (1,2,4).…”

Invasion of Eukaryotic Cells byBorrelia burgdorferiRequires β1Integrins and Src Kinase Activity

“…The alternative ␣ subunit that engages the ␤ 1 subunit for borrelial invasion is not known but, based on known expression profiles of fibroblasts, may be the ␣ 1 , ␣ 2 , ␣ 3 , ␣ 8 , or ␣ 11 subunit (11,15,42,48,83,85). Recently ␣ 3 ␤ 1 -B. burgdorferi interactions were reported for chondrocytes (7,8), and given the abundance of ␣ 3 ␤ 1 in a number of cell types (21,45,49,82), as well as the ability of ␣ 3 ␤ 1 to bind a large number of extracellular matrix proteins, including fibronectin, laminin, and collagen (22,26,88), it is possible that ␣ 3 ␤ 1 may mediate the B. burgdorferi-host cell interaction observed.…”

Importance of integrin receptors in the field of pharmaceutical & medical science

“…We have discussed the role of integrin αvβ3 in the development osteoporosis. Recently Lemieux et al reported the involvement of α3β1 & α5β1 in the development of osteoporosis [207]. They found that these two integrins are expressed on the surface of hematopoietic cell, like megakaryocytes and play a crucial role in the megakaryocyte cell mediated osteoblast differentiation.…”