Bone Morphogenetic Protein Type IA Receptor Signaling Regulates Postnatal Osteoblast Function and Bone Remodeling

Abstract

Bone morphogenetic proteins (BMPs) function during various aspects of embryonic development including skeletogenesis. However, their biological functions after birth are less understood. To investigate the role of BMPs during bone remodeling, we generated a postnatal osteoblast-specific disruption of Bmpr1a that encodes the type IA receptor for BMPs in mice. Mutant mice were smaller than controls up to 6 months after birth. Irregular calcification and low bone mass were observed, but there were normal numbers of osteoblasts. The ability of the mutant osteoblasts to form mineralized nodules in culture was severely reduced. Interestingly, bone mass was increased in aged mutant mice due to reduced bone resorption evidenced by reduced bone turnover. The mutant mice lost more bone after ovariectomy likely resulting from decreased osteoblast function which could not overcome ovariectomyinduced bone resorption. In organ culture of bones from aged mice, ablation of the Bmpr1a gene by adenoviral Cre recombinase abolished the stimulatory effects of BMP4 on the expression of lysosomal enzymes essential for osteoclastic bone resorption. These results demonstrate essential and age-dependent roles for BMP signaling mediated by BMPRIA (a type IA receptor for BMP) in osteoblasts for bone remodeling.Bone formation is a well characterized process; however, little is known about the molecular mechanisms that regulate bone remodeling, the physiological process through which bone mass is maintained constant. Remodeling consists of two distinct phases: initial bone resorption by the osteoclasts, followed by de novo bone formation by the osteoblasts (1). Differentiated osteoblasts are the only cells responsible for bone formation. Bone formation is thought to be regulated by hormones and by locally acting growth factors (2). Bone morphogenetic proteins (BMPs) 1 are secreted molecules and members of transforming growth factor-␤ superfamily (3, 4). They were discovered by their ectopic bone formation activity when implanted locally in soft tissues (5). Over the past decade, the phenotypes of mice with mutations in genes coding for this group of proteins and their receptors uncovered the essential roles for BMPs in wide variety of developmental processes, including skeletal development and patterning (6 -9). However, despite its powerful ability to induce ectopic osteogenesis, the essential role of BMPs in bone formation and bone metabolism in the adult skeleton has not been established (10) because of embryonic lethality resulting from mutations of genes encoding the most potent BMPs for bone formation, BMP2 and BMP4, and their receptors (11-13). We previously generated a null allele for Bmpr1a that encodes a type IA receptor for BMP (BMPRIA or ALK3). Mice homozygous for this null allele died by embryonic day 8.0 (E8.0) without mesoderm formation (13). Bmpr1a is expressed in most tissues throughout development and after birth (13,14). Expression of a dominant-negative form of BMPRIA in a cultured cell line or chick limb buds suggests ...

A Lox/CHOP‐10 crosstalk governs osteogenic and adipogenic cell fate by MSCs

“…Recently, it has been demonstrated that increased circulating levels of BMP4 in obese human subjects and diet‐induced obesity (DIO) mice,37, 38 which is often accompanied with osteoporosis, suggesting a osteoporosis promotion role of BMP4. Furthermore, disruption of signalling through BMPR1A in adult osteoblasts or osteoclasts39, 40, 41 increases bone mass provides evidence that alteration of the physiologic levels of BMPs and/or altering BMPR1A may have therapeutic effects on bone loss in vivo. Our findings reveal that Lox inhibition promotes BMP4‐induced osteogenesis, which contradicts previous reports about the functions of Lox in bone development 14, 42, 43, 44.…”

AP2γ regulates neural and epidermal development downstream of the BMP pathway at early stages of ectodermal patterning

“…Here, we identified AP2γ as a novel BMP downstream target that is directly regulated by BMP4 through Smad1 binding to the AP2γ promoter (Figure 7). BMPR1a-knockout mice die at E8.0 while BMPR1b-null mice are viable [71,72], implying that BMPR1a was the possible receptor mediating BMP functions during ectodermal patterning. In the early chick embryo, cAP2γ can be ectopically induced by BMP4 and suppressed by chordin (Figure 6), suggesting that clearance of AP2γ transcripts from the medial epiblast might be elicited by BMP antagonists secreted from the organizer with gradually enhanced expression [63,73].…”

BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells

“…Blockage of BMP-2 action by the antagonist, noggin, inhibits osteoblast differentiation and bone formation in vivo and in vitro [9]. Interruption of the receptor signal by targeted-deletion of BMP type I receptor results in reduced mineralization and bone mass [10]. Recently, several studies have suggested that BMP-2 may also be important in vascular calcification under pathological conditions.…”