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Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n= 20) or placebo (n= 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n= 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET–CT) was not met (P= 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P= 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666.

In this study, we leveraged the combined evidence of rare coding variants and common alleles to identify therapeutic targets for osteoporosis. We undertook a large-scale multiancestry exome-wide association study for estimated bone mineral density, which showed that the burden of rare coding alleles in 19 genes was associated with estimated bone mineral density (P< 3.6 × 10–7). These genes were highly enriched for a set of known causal genes for osteoporosis (65-fold; P= 2.5 × 10–5). Exome-wide significant genes had 96-fold increased odds of being the top ranked effector gene at a given GWAS locus (P= 1.8 × 10–10). By integrating proteomics Mendelian randomization evidence, we prioritized CD109(cluster of differentiation 109) as a gene for which heterozygous loss of function is associated with higher bone density. CRISPR–Cas9 editing of CD109in SaOS-2 osteoblast-like cell lines showed that partial CD109 knockdown led to increased mineralization. This study demonstrates that the convergence of common and rare variants, proteomics and CRISPR can highlight new bone biology to guide therapeutic development.

Sensorimotor information processing underlies normal cognitive and behavioral traits and has classically been evaluated through prepulse inhibition (PPI) of a startle reflex. PPI is a behavioral dimension deregulated in several neurological and psychiatric disorders, yet the mechanisms underlying the cross-diagnostic nature of PPI deficits across these conditions remain to be understood. To identify circuitry mechanisms for PPI, we performed circuitry recording over the prefrontal cortex and striatum, two brain regions previously implicated in PPI, using wild-type (WT) mice compared to Disc1-locus-impairment (LI) mice, a model representing neuropsychiatric conditions. We demonstrated that the corticostriatal projection regulates neurophysiological responses during the PPI testing in WT, whereas these circuitry responses were disrupted in Disc1-LI mice. Because our biochemical analyses revealed attenuated brain-derived neurotrophic factor (Bdnf) transport along the corticostriatal circuit in Disc1-LI mice, we investigated the potential role of Bdnf in this circuitry for regulation of PPI. Virus-mediated delivery of Bdnf into the striatum rescued PPI deficits in Disc1-LI mice. Pharmacologically augmenting Bdnf transport by chronic lithium administration, partly via phosphorylation of Huntingtin (Htt) serine-421 and its integration into the motor machinery, restored striatal Bdnf levels and rescued PPI deficits in Disc1-LI mice. Furthermore, reducing the cortical Bdnf expression negated this rescuing effect of lithium, confirming the key role of Bdnf in lithium-mediated PPI rescuing. Collectively, the data suggest that striatal Bdnf supply, collaboratively regulated by Htt and Disc1 along the corticostriatal circuit, is involved in sensorimotor gating, highlighting the utility of dimensional approach in investigating pathophysiological mechanisms across neuropsychiatric disorders.

Lysosomal diseases are a class of genetic disorders predominantly caused by loss of lysosomal hydrolases, leading to lysosomal and cellular dysfunction. Enzyme replacement therapy (ERT), where recombinant enzyme is given intravenously, internalized by cells, and trafficked to the lysosome, has been applied to treat several lysosomal diseases. However, current ERT regimens do not correct disease phenotypes in all affected organs because the biodistribution of enzyme uptake does not match that of the affected cells that require the enzyme. We present here targeted ERT, an approach that utilizes antibody-enzyme fusion proteins to target the enzyme to specific cell types. The antibody moiety recognizes transmembrane proteins involved in lysosomal trafficking and that are also preferentially expressed in those cells most affected in disease. Using Pompe disease (PD) as an example, we show that targeted ERT is superior to ERT in treating the skeletal muscle phenotypes of PD mice both as a protein replacement therapeutic and as a gene therapy.

Noncoding RNAs are exquisitely titrated by the cellular RNA surveillance machinery for regulating diverse biological processes. The RNA exosome, the predominant 3' RNA exoribonuclease in mammalian cells, is composed of nine core and two catalytic subunits. Here, we developed a mouse model with a conditional allele to study the RNA exosome catalytic subunit DIS3. In DIS3-deficient B cells, integrity of the immunoglobulin heavy chain (Igh) locus in its topologically associating domain is affected, with accumulation of DNA-associated RNAs flanking CTCF-binding elements, decreased CTCF binding to CTCF-binding elements and disorganized cohesin localization. DIS3-deficient B cells also accumulate activation-induced cytidine deaminase–mediated asymmetric nicks, altering somatic hypermutation patterns and increasing microhomology-mediated end-joining DNA repair. Altered mutation patterns and Igharchitectural defects in DIS3-deficient B cells lead to decreased class-switch recombination but increased chromosomal translocations. Our observations of DIS3-mediated architectural regulation at the Ighlocus are reflected genome wide, thus providing evidence that noncoding RNA processing is an important mechanism for controlling genome organization.

Previously we reported the identification of a homozygous COL27A1(c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

Mice harboring Notch2mutations replicating Hajdu-Cheney syndrome (Notch2tm1.1ECan) have osteopenia and exhibit an increase in splenic marginal zone B cells with a decrease in follicular B cells. Whether the altered B-cell allocation is responsible for the osteopenia of Notch2tm1.1ECanmutants is unknown. To determine the effect of NOTCH2 activation in B cells on splenic B-cell allocation and skeletal phenotype, a conditional-by-inversion (COIN) Hajdu-Cheney syndrome allele of Notch2(Notch2[ΔPEST]COIN) was used. Cre recombination generates a permanent Notch2ΔPESTallele expressing a transcript for which sequences coding for the proline, glutamic acid, serine, and threonine–rich (PEST) domain are replaced by a stop codon. CD19-Credrivers were backcrossed into Notch2[ΔPEST]COIN/[ΔPEST]COINto generate CD19-specific Notch2ΔPEST/ΔPESTmutants and control Notch2[ΔPEST]COIN/[ΔPEST]COINlittermates. There was an increase in marginal zone B cells and a decrease in follicular B cells in the spleen of CD19Cre/WT;Notch2ΔPEST/ΔPESTmice, recapitulating the splenic phenotype of Notch2tm1.1ECanmice. The effect was reproduced when the NOTCH1 intracellular domain was induced in CD19-expressing cells (CD19Cre/WT;RosaNotch1/WTmice). However, neither CD19Cre/WT;Notch2ΔPEST/ΔPESTnor CD19Cre/WT;RosaNotch1/WTmice had a skeletal phenotype. Moreover, splenectomies in Notch2tm1.1ECanmice did not reverse their osteopenic phenotype. In conclusion, Notch2 activation in CD19-expressing cells determines B-cell allocation in the spleen but has no skeletal consequences.

The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.

The bone marrow niche is thought to act as a permissive microenvironment required for emergence or progression of hematologic cancers. We hypothesized that osteoblasts, components of the niche involved in hematopoietic stem cell (HSC) function, influence the fate of leukemic blasts. We show that osteoblast numbers decrease by 55% in myelodysplasia and acute myeloid leukemia patients. Further, genetic depletion of osteoblasts in mouse models of acute leukemia increased circulating blasts and tumor engraftment in the marrow and spleen leading to higher tumor burden and shorter survival. Myelopoiesis increased and was coupled with a reduction in B lymphopoiesis and compromised erythropoiesis, suggesting that hematopoietic lineage/progression was altered. Treatment of mice with acute myeloid or lymphoblastic leukemia with a pharmacologic inhibitor of the synthesis of duodenal serotonin, a hormone suppressing osteoblast numbers, inhibited loss of osteoblasts. Maintenance of the osteoblast pool restored normal marrow function, reduced tumor burden, and prolonged survival. Leukemia prevention was attributable to maintenance of osteoblast numbers because inhibition of serotonin receptors alone in leukemic blasts did not affect leukemia progression. These results suggest that osteoblasts play a fundamental role in propagating leukemia in the marrow and may be a therapeutic target to induce hostility of the niche to leukemia blasts.

Beta-thalassemia is a hereditary iron-independent anemia, caused by a reduction of β-globin, affecting millions of people globally. Current treatments such as blood transfusions and iron chelation show significant toxicities and add to organ damage. Luspatercept (Acvr2b(L79D)-Fc) is a novel treatment for transfusion-dependent β-thalassemia patients that improves erythropoiesis independent of erythropoietin. The exact mechanism of action remains unknown, and it is controversially discussed if growth differentiation factor 11 (GDF11) is the main target of this drug. Genetic models raised doubts that GDF11 is the target of Acvr2b(L79D)-Fc. Here we tested if a GDF11 specific blocking antibody improves β-thalassemia intermedia in mice. Our findings support the genetic data that GDF11 does not play a role in the ineffective erythropoiesis in β-thalassemia. Anti-GDF11 treatment did not change hematocrit, hemoglobin and red blood cell number and it did not improve erythropoiesis. Ex vivotreatment of erythroblasts with recombinant GDF11 did not inhibit red blood cell maturation. Lastly, we identified that inhibiting GDF8 in β-thalassemia mice has a small effect on erythropoiesis and increased hemoglobin levels without being as effective as Acvr2b(L79D)-Fc. Of note, wild-type animals treated with anti-GDF8 did not show changes in any hematology parameters and therefore the small effect we observed might be due to the disease phenotype, but not due to a physiological mechanism involved in erythropoiesis. Taken together, GDF11 is not involved in erythropoiesis but GDF8 may have a minor role in the regulation of ineffective erythropoiesis. Given the small effect of anti-GDF8 on erythropoiesis compared to Acvr2b(L79D)-Fc, we conclude that either there is another target or several targets of Acvr2b(L79D)-Fc driving ineffective erythropoiesis, or that Acvr2b(L79D)-Fc efficacy is due to it altering the overall BMP/GDF/Activin ligand and receptor balance.

Lob: Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Kravets:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Miloscio:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Mastaitis:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Economides:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hatsell:Regeneron Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Huntington’s disease (HD) is a neurodegenerative disease characterized in part by the loss of striatopallidal medium spiny projection neurons (MSNs). Expression of BDNF and noggin via intracerebroventricular (ICV) delivery in an adenoviral vector triggers the addition of new neurons to the neostriatum. In this study, we found that a single ICV injection of the adeno-associated viruses AAV4-BDNF and AAV4-noggin triggered the sustained recruitment of new MSNs in both wild-type and R6/2 mice, a model of HD. Mice treated with AAV4-BDNF/noggin or with BDNF and noggin proteins actively recruited subependymal progenitor cells to form new MSNs that matured and achieved circuit integration. Importantly, the AAV4-BDNF/noggin-treated R6/2 mice showed delayed deterioration of motor function and substantially increased survival. In addition, squirrel monkeys given ICV injections of adenoviral BDNF/noggin showed similar addition of striatal neurons. Induced neuronal addition may therefore represent a promising avenue for disease amelioration in HD.

The transforming growth factor beta (TGFB) protein family is renowned for its diverse roles in developmental biology including reproduction. Gremlin is a member of the differential screening-selected gene aberrative in neuroblastoma (DAN)/cerberus family of bone morphogenetic protein (BMP) antagonists. Recent studies on gremlin focus on its involvement in embryonic skeletal, lung, and kidney development. To define the role of gremlin (Grem1) in female reproduction, we analyzed postnatal folliculogenesis using global and conditional knockout (cKO) mice for gremlin. Grem1−/−mice die within 48 h after birth, and ovaries collected from neonatal Grem1−/−mice demonstrated reduced oocyte numbers and delayed primordial follicle development. Transplanting Grem1−/−neonatal ovaries showed that folliculogenesis proceeded to large antral follicle stage, but Grem1−/−ovaries contained corpora lutea-like structures not found in control-transplanted ovaries. However, Grem1cKO mice had comparable fertility to control mice. These data suggest that gremlin plays a previously uncharacterized role in the regulation of oocyte numbers and the timing of primordial follicle development, but either it is not required for later folliculogenesis or its loss is possibly compensated by other BMP antagonists.

Bone morphogenetic proteins (BMPs) are expressed broadly and regulate a diverse array of developmental events in vivo. Essential to many of these functions is the establishment of activity gradients of BMP, which provide positional information that influences cell fates. Secreted polypeptides, such as Noggin, bind BMPs and inhibit their function by preventing interaction with receptors on the cell surface. These BMP antagonists are assumed to be diffusible and therefore potentially important in the establishment of BMP activity gradients in vivo. Nothing is known, however, about the potential interactions between Noggin and components of the cell surface or extracellular matrix that might limit its diffusion. We have found that Noggin binds strongly to heparin in vitro, and to heparan sulfate proteoglycans on the surface of cultured cells. Noggin is detected only on the surface of cells that express heparan sulfate, can be specifically displaced from cells by heparin, and can be directly cross-linked to a cell surface proteoglycan in culture. Heparan sulfate-bound Noggin remains functional and can bind BMP4 at the plasma membrane. A Noggin mutant with a deletion in a putative heparin binding domain has reduced binding to heparin and does not bind to the cell surface but has preserved BMP binding and antagonist functions. Our results imply that interactions between Noggin and heparan sulfate proteoglycans in vivoregulate diffusion and therefore the formation of gradients of BMP activity.

Bone morphogenetic proteins (BMPs) are expressed and secreted during fracture repair. Although they are likely to be required for this process, little is known about their physiological role in bone regeneration. Noggin is a protein that specifically binds and inactivates several BMPs. It plays fundamental roles during early embryonal development and limb morphogenesis by this BMP‐inactivating activity. This study shows that Noggin can modify bone formation in vivo in the adult animal and, thus, indirectly, that BMP signaling is indispensable in this process. A noggin mutein (hNgΔB2‐Fc) engineered so as to display increased bioavailability was used. Bilateral titanium bone chambers were inserted in 70 rats, and side comparisons for bone formation in the chambers were done. The hNgΔB2‐Fc had no effect on total amount of tissue formed in the chamber but decreased the amount of bone compared with both buffer controls and a control made up of an Fc‐tagged IL‐6Rα protein, which had no effects of its own. Also, wild‐type noggin inhibited bone formation. Thus, endogenous BMP signaling is necessary for normal bone regeneration.

Bone morphogenetic proteins (BMPs) are expressed and secreted during fracture repair. Although they are likely to be required for this process, little is known about their physiological role in bone regeneration. Noggin is a protein that specifically binds and inactivates several BMPs. It plays fundamental roles during early embryonal development and limb morphogenesis by this BMP‐inactivating activity. This study shows that Noggin can modify bone formation in vivo in the adult animal and, thus, indirectly, that BMP signaling is indispensable in this process. A noggin mutein (hNgΔB2‐Fc) engineered so as to display increased bioavailability was used. Bilateral titanium bone chambers were inserted in 70 rats, and side comparisons for bone formation in the chambers were done. The hNgΔB2‐Fc had no effect on total amount of tissue formed in the chamber but decreased the amount of bone compared with both buffer controls and a control made up of an Fc‐tagged IL‐6Rα protein, which had no effects of its own. Also, wild‐type noggin inhibited bone formation. Thus, endogenous BMP signaling is necessary for normal bone regeneration.

Bone morphogenetic proteins (BMPs) have been heretofore implicated in the induction of osteoblast differentiation from uncommitted progenitors during embryonic skeletogenesis and fracture healing. We have tested the hypothesis that BMPs are also involved in the osteoblastogenesis that takes place in the bone marrow in postnatal life. To do this, we took advantage of the properties of noggin, a recently discovered protein that binds BMP‐2 and −4 and blocks their action. Addition of human recombinant noggin to bone marrow cell cultures from normal adult mice inhibited both osteoblast and osteoclast formation; these effects were reversed by exogenous BMP‐2. Consistent with these findings, BMP‐2 and −4 and BMP‐2/4 receptor transcripts and proteins were detected in these primary cultures, in a bone marrow–derived stromal/osteoblastic cell line, as well as in murine adult whole bone; noggin expression was also documented in all these preparations. Moreover, addition of antinoggin antibody caused an increase in osteoblast progenitor formation. These findings suggest that BMP‐2 and −4 are expressed in the bone marrow in postnatal life and serve to maintain the continuous supply of osteoblasts and osteoclasts; and that, in fact, BMP‐2/4‐induced commitment to the osteoblastic lineage is a prerequisite for osteoclast development. Hence, BMPs, perhaps in balance with noggin and possibly other antagonists, may provide the tonic baseline control of the rate of bone remodeling on which other inputs (e.g., hormonal, biomechanical, etc.) operate.

Bone morphogenetic proteins (BMPs) have been heretofore implicated in the induction of osteoblast differentiation from uncommitted progenitors during embryonic skeletogenesis and fracture healing. We have tested the hypothesis that BMPs are also involved in the osteoblastogenesis that takes place in the bone marrow in postnatal life. To do this, we took advantage of the properties of noggin, a recently discovered protein that binds BMP‐2 and −4 and blocks their action. Addition of human recombinant noggin to bone marrow cell cultures from normal adult mice inhibited both osteoblast and osteoclast formation; these effects were reversed by exogenous BMP‐2. Consistent with these findings, BMP‐2 and −4 and BMP‐2/4 receptor transcripts and proteins were detected in these primary cultures, in a bone marrow–derived stromal/osteoblastic cell line, as well as in murine adult whole bone; noggin expression was also documented in all these preparations. Moreover, addition of antinoggin antibody caused an increase in osteoblast progenitor formation. These findings suggest that BMP‐2 and −4 are expressed in the bone marrow in postnatal life and serve to maintain the continuous supply of osteoblasts and osteoclasts; and that, in fact, BMP‐2/4‐induced commitment to the osteoblastic lineage is a prerequisite for osteoclast development. Hence, BMPs, perhaps in balance with noggin and possibly other antagonists, may provide the tonic baseline control of the rate of bone remodeling on which other inputs (e.g., hormonal, biomechanical, etc.) operate.

The mature C-terminal signaling domain of theDrosophilaDecapentaplegic proprotein (DPP) can be efficiently refolded from chaotrope-solubilized inclusion bodies with the aid of a membrane protein-solubilizing detergent, high concentrations (0.75–2 m) of NaCl, and low temperatures (5–15 °C). The disulfide-linked homodimeric product contains N-terminal heparin-binding sites that were utilized as intrinsic affinity tags to obtain a highly enriched preparation in one chromatographic step. A subsequent C4 reverse phase high pressure liquid chromatography step provides high purity, salt-free protein that is amenable to biophysical and structural studies at a yield of approximately 3 mg/liter of bacterial culture. The dimeric protein is correctly folded as determined by electrophoretic, spectroscopic, chemical, and proteolytic analyses. Refolded DPP is also bioactive as shown by induction of chondrogenesis in embryonic chick limb bud cells and by high affinity binding to Noggin, an antagonist of bone morphogenetic protein signaling. In contrast to bone morphogenetic proteins extracted from demineralized bone or overexpressed in cell culture, the refolded Escherichia coli-expressed protein is not glycosylated at a conserved N-linked site and is therefore homogeneous. The C-terminal domain dimer is more hydrophobic and thus less soluble than its unfolded or partially folded forms, necessitating highly solubilizing conditions for recovery after foldingin vitro. Hence solubilization of the mature ligand may be one of the principal roles of the large (250–400 amino acids) N-terminal prodomains of transforming growth factor-β superfamily members, shown to act as intramolecular chaperones in vivo.

Using a Xenopusexpression-cloning screen, we have isolated Gremlin, a novel antagonist of bone morphogenetic protein (BMP) signaling that is expressed in the neural crest. Gremlinbelongs to a novel gene family that includes the head-inducing factor Cerberusand the tumor suppressor DAN. We show that all family members are secreted proteins and that they act as BMP antagonists in embryonic explants. We also provide support for the model that Gremlin, Cerberus, and DAN block BMP signaling by binding BMPs, preventing them from interacting with their receptors. In addition, Cerberus alone blocks signaling by Activin- and Nodal-like members of the TGFβ superfamily. Therefore, we propose that Gremlin, Cerberus, and DAN control diverse processes in growth and development by selectively antagonizing the activities of different subsets of TGFβ ligands.

In the final stages of limb morphogenesis, autopodial cells leaving the progress zone differentiate into cartilage or undergo apoptotic cell death, depending on whether they are incorporated into the digital rays or interdigital spaces. Most evidence indicates that these two opposite fates of the autopodial mesoderm are controlled by BMP signaling. However, the molecular basis for these two distinct actions of BMPs, including the receptors involved in the process, is controversial. In this study we have addressed this question by exploring the presence in the developing autopod of diffusible signals able to modulate BMP function and by analyzing the effects of their exogenous administration on the pattern of expression of BMP receptor genes. Our findings show thattgfβ2andnoggingenes are expressed in the condensing region of the developing digital rays in addition to the well-known distribution in the autopodial tissues of FGFs (apical ectodermal ridge, AER) and BMPs (AER, progress zone mesoderm, and interdigital regions). Exogenous administration of all the factors causes changes in the expression of thebmpR-1bgene which are followed by parallel alterations of the skeletal phenotype: FGFs inhibit the expression ofbmpR-1bcompatible with their function in the maintenance of the progress zone mesoderm in an undifferentiated state; and TGFβs induce the expression ofbmpR-1band promote ectopic chondrogenesis, compatible with a function in the establishment of the position of the digital rays. In addition we provide evidence for the occurrence of an interactive loop between BMPs and noggin accounting for the spatial distribution ofbmpR-1bwhich may control the size and shape of the skeletal pieces. In contrast to thebmpR-1bgene, thebmpR-1agene is expressed at low levels in the autopodial mesoderm and its expression is not modified by any of the tested factors regardless of their effects on chondrogenesis or cell death. Finally, the role of BMPs in programmed cell death is confirmed here by the intense inhibitory effect of noggin on apoptosis, but the lack of correlation between changes in the pattern of cell death induced by treatment with the studied factors and the expression of eitherbmpR-1aorbmpR-1bgenes suggest that a still-unidentified BMP receptor may account for this BMP function.

Tissue-specific manifestations of the congenital bone-forming syndrome FOP are mediated by multiple tissue-resident stem cell populations.

In patients with fibrodysplasia ossificans progressiva, the disease-causing mutation changes the ligand response profile of the ACVR1 receptor so that it is activated by the normally antagonistic ligand activin A.