Turning Bone Morphogenetic Protein 2 (BMP2) on and off in Mesenchymal Cells

Abstract

The concentration, location, and timing of bone morphogenetic protein 2 (BMP2, HGNC:1069, GeneID: 650) gene expression must be precisely regulated. Abnormal BMP2 levels cause congenital anomalies and diseases involving the mesenchymal cells that differentiate into muscle, fat, cartilage, and bone. The molecules and conditions that influence BMP2 synthesis are diverse. Understandably, complex mechanisms control Bmp2 gene expression. This review includes a compilation of agents and conditions that can induce Bmp2. The currently known trans-regulatory factors and cis-regulatory elements that modulate Bmp2 expression are summarized and discussed. This article is protected by copyright. All rights reserved

Structural determinants and genetic modifications enhance BMP2 stability and extracellular secretion

“…15,[33][34][35][36] Half-life of nascent BMP2 in circulation is very short and therefore there have been many approaches that have addressed this limitation by facilitating its sustained delivery with help of specialized bio-inductive scaffolds. Although transcriptional regulation and proteolytic processing of BMP2 has been investigated in detail, studies dissecting its intracellular degradation and its effect on extracellular secretion are lacking.…”

“…11,12 To overcome issues related to its suboptimal delivery, retention scaffolds are coated with supraphysiological amounts of the protein. 7,14,15 Some of these studies have also focused on improving BMP2 stability in solution, on retention scaffolds, and in the circulation. 7,14,15 Some of these studies have also focused on improving BMP2 stability in solution, on retention scaffolds, and in the circulation.…”

Effects of local delivery of BMP2, zoledronate and their combination on bone microarchitecture, biomechanics and bone turnover in osteoporotic rabbits

“…BMPs are members of the transforming growth factor-β gene superfamily, which have exhibited notably stimulating effects on fracture healing, critical-sized bone defect repair and osteoporosis both experimentally and clinically via their strong anabolic actions678. BMP2 has the capacity of initiating a cascade of intracellular biochemical responses, resulting in the recruitment and differentiation of mesenchymal progenitor cells into osteoblasts89. BMP2 can also promote the biological functions of osteoblasts, and consequently accelerate the formation of bone matrix1011.…”

Local and targeted drug delivery for bone regeneration

“…Additional gains in uniformity have been achieved through GMP-compliant isolation procedures [8], culture conditions [9,10], and cryopreservation techniques [11,12]. There are now Food and Drug Administration GMP-approved facilities (the NIH BMSC Transplantation Center and the Upstate New York Stem Cell cGMP Facility) that generate MSCs for clinical investigations [13 • ]. However, cell-based therapies require significant lead-time to achieve cell quantities necessary for many regenerative approaches [14].…”

“…Based on these factors, a variety of drugs, including BMPs, other growth factors, hormones, and monoclonal antibodies, have been explored for bone regenerative effects [20,23 • ]. Common strategies focus on BMP therapy, as canonical BMP signaling is integral to bone formation [13 • ,24 • ]. In fact, drug delivery approaches that increase the availability of factors such as BMP2 have been proven safe and efficacious for bone regeneration (e.g., INFUSE™ [6]); however, protein (e.g., antibodies, growth factors) half-lives are only on the order of an hour [25], necessitating local delivery of supra-physiological doses to achieve desired pharmacodynamics.…”