Activity Of Bone Morphogenetic Protein-7 Research Articles

Bone Morphogenetic Protein 7 Effect on Human Glioblastoma Cell Transmigration and Migration.

Glioblastoma, World Health Organization—grade IV, is the most malignant glioma type and it is still an incurable tumor due to the high level of heterogeneity and uncontrolled metastatic nature. In addition to the tumorigenicity-suppressing activity, bone morphogenetic protein 7 (BMP7) has recently been found for its invasion-promoting role in glioblastoma. However, the detailed and precise mechanism in this issue should have more elucidation. Thus, in this study, we determined the BMP7 effect on glioblastoma transmigration and migration regulations and the underlying mechanisms. Human LN18/LN229 glioblastoma cells were used in this study. Our results showed a higher BMP7/pSmad5 level in human malignant glioma tissues compared to healthy brain tissues. In addition, it was demonstrated that endogenous and exogenous BMP7 stimulation could increase the transmigration and migration capabilities of human LN18/LN229 glioblastoma cells. Moreover, this event is regulated by Smad5 and p75 neurotrophin receptor (p75NTR) signaling. Furthermore, unexpected data are that the Smad1 gene knockdown could lead to the cell death of human LN18 glioblastoma cells. Overall, the present study finds that the invasion-promoting activity of BMP7 might be an autocrine stimulation of glioblastoma and this effect could be regulated by Smad5-p75NTR signaling.

Canonical BMP signaling in tubular cells mediates recovery after acute kidney injury

Bone morphogenetic protein (BMP) signaling has been shown to modulate the development of renal fibrosis in animal models of kidney injury, but the downstream mediators are incompletely understood. In wild-type mice, canonical BMP signaling mediated by SMAD1/5/8 transcription factors was constitutively active in healthy renal tubules, transiently down-regulated after ischemia reperfusion injury (IRI), and reactivated during successful tubular regeneration. We then induced IRI in mice with a tubular-specific BMP receptor 1A (BMPR1A) deletion. These mice failed to reactivate SMAD1/5/8 signaling in the post-ischemic phase and developed renal fibrosis after injury. Using unbiased genomic analyses, we identified three genes encoding inhibitor of DNA-binding (ID) proteins (Id1, Id2, and Id4) as key targets of BMPR1A-SMAD1/5/8 signaling. BMPR1A-deficient mice failed to re-induce these targets following IRI. Instead, BMPR1A-deficiency resulted in activation of pro-fibrotic signaling proteins that are normally repressed by ID proteins, namely, p38 mitogen-activated protein kinase and cell cycle inhibitor p27. These data indicate that the post-ischemic activation of canonical BMP signaling acts endogenously to repress pro-fibrotic signaling in tubular cells and may help to prevent the progression of acute kidney injury to chronic kidney disease.

Increased bone morphogenetic protein 7 signalling in the kidneys of dogs affected with a congenital portosystemic shunt

Dogs with a congenital portosystemic shunt (CPSS) often have enlarged and hyper-filtrating kidneys. Although expression of different growth factors has been well-described in the livers of dogs affected with a CPSS, their expression in the kidneys has yet to be determined. Bone morphogenetic protein 7 (BMP-7), hepatocyte growth factor (HGF) and transforming growth factor (TGF)-β have been implicated in renal development (BMP-7, HGF) or the onset of renal fibrosis (TGF-β). Moreover, BMP-7 and HGF have protective properties in renal fibrosis.In this study, the expression and activity of BMP-7 were investigated in renal biopsies obtained from 13 dogs affected with a CPSS and compared to similar samples from age-matched healthy control dogs. Both quantitative reverse-transcriptase PCR and Western blotting showed up-regulated BMP-7 signalling in kidneys of CPPS-affected dogs. These research findings may help to explain the renal pathology/dysfunction in dogs affected with a CPSS.

Lactoferricin enhances BMP7-stimulated anabolic pathways in intervertebral disc cells

Bone-morphogenetic protein-7 (BMP7) is a well-known anabolic and anti-catabolic growth factor on intervertebral disc (IVD) matrix and cell homeostasis. Similarly, Lactoferricin B (LfcinB) has recently been shown to have pro-anabolic, anti-catabolic, anti-oxidative and/or anti-inflammatory effects in bovine disc cells in vitro. In this study, we investigated the potential benefits of using combined peptide therapy with LfcinB and BMP7 for intervertebral disc matrix repair and to understand cellular and signaling mechanisms controlled by these factors. We studied the effects of BMP7 and LfcinB as individual treatments and combined therapy on bovine nucleus pulposus (NP) cells by assessing proteoglycan (PG) accumulation and synthesis, and the gene expression of matrix protein aggrecan and transcription factor SOX-9. We also analyzed the role of Noggin, a BMP antagonist, in IVD tissue and examined its effect after stimulation with LfcinB. To understand the molecular mechanisms by which LfcinB synergizes with BMP7, we investigated the ERK-SP1 axis as a downstream intracellular signaling regulator involved in BMP7 and LfcinB-mediated activities. Treatment of bovine NP cells cultured in alginate with LfcinB plus BMP7 synergistically stimulates PG synthesis and accumulation in part by upregulation of aggrecan gene expression. The synergism results from LfcinB-mediated activation of Sp1 and SMAD signaling pathways by (i) phosphorylation of SMAD 1/5/8; (ii) downregulation of SMAD inhibitory factors [i.e., noggin and SMAD6 (inhibitory SMAD)]; and (iii) upregulation of SMAD4 (universal co-SMAD). These data indicate that LfcinB-suppression of Noggin may eliminate the negative feedback of BMP7, thereby maximizing biological activity of BMP7 and ultimately shifting homeostasis to a pro-anabolic state in disc cells. We propose that combination growth factor therapy using BMP7 and LfcinB may be beneficial for treatment of disc degeneration.

Fractone-heparan sulfates mediate BMP-7 inhibition of cell proliferation in the adult subventricular zone

Bone morphogenetic protein-7 (BMP-7) is a heparin-binding growth factor that inhibits cell proliferation in the subventricular zone (SVZ) of the lateral ventricle, the primary neurogenic niche in the adult brain. However, the physiological mechanisms regulating the activity of BMP-7 in the SVZ are unknown. Here, we report the inhibitory effect of BMP-7 on cell proliferation through the anterior SVZ after intracerebroventricular injection in the adult mouse. To determine whether the inhibition of cell proliferation induced by BMP-7 is dependant on heparin-binding, heparitinase-1 was intracerebroventricularly injected to N-desulfate heparan sulfate proteoglycans before BMP-7 was injected. Heparatinase-1 drastically reduced the inhibitory effect of BMP-7 on cell proliferation in the SVZ. To determine where BMP-7 binds within the niche, we visualized biotinylated-BMP-7 after intracerebroventricular injection, using streptavidin Texas red on frozen brain sections. BMP-7 binding was seen as puncta in the SVZ at the location of fractones, the particulate specialized extracellular matrix of the SVZ, which have been identified primarily by N-sulfated heparan sulfate immunoreactivity (NS-HS+). BMP binding was also seen in NS-HS+ blood vessels of the SVZ. Injection of heparitinase-1 prior to biotinylated BMP-7 resulted in the absence of signal for biotinylated-BMP-7 in the fractones and blood vessels, indicating that the binding is heparan sulfate dependant. These results indicate that BMP-7 requires heparan sulfates to bind and inhibit cell proliferation in the SVZ neurogenic niche. Heparan sulfates concentrated in fractones and SVZ blood vessels emerge as a functional stem cell niche component involved in growth factor activity.

Gremlin-mediated decrease in bone morphogenetic protein signaling promotes aristolochic acid-induced epithelial-to-mesenchymal transition (EMT) in HK-2 cells

Ingestion of aristolochic acid (AA) is associated with the development of aristolochic acid nephropathy (AAN), which is characterized by progressive tubulointerstitial fibrosis, chronic renal failure and urothelial cancer. Our previous study showed that bone morphogenetic protein-7 (BMP-7) could attenuate AA-induced epithelial-to-mesenchymal transition (EMT) in human proximal tubule epithelial cells (PTEC). However, how gremlin (a BMP-7 antagonist) antagonizes the BMP-7 action in PTEC remained unsolved. The aim of the current study was to investigate the role of gremlin in AA-induced EMT in PTEC (HK-2 cells). HK-2 cells were treated with AA (10μmol/L) for periods up to 72h. Cell viability was determined by tetrazolium dye (MTT) assay. Morphological changes were assessed by phase-contrast microscopy. Markers of EMT, including E-cadherin and α-smooth muscle actin (α-SMA) were detected by indirect immunofluorescence stains. The BMP-7 and gremlin mRNA and protein expression in HK-2 cells were analyzed by quantitative real-time PCR (real-time RT-PCR) and western blotting after exposure to AA. The level of phosphorylated Smad1/5/8, a marker of BMP-7 activity, was also determined by western blot analysis. Cells were transfected with gremlin siRNA to determine the effects of gremlin knockdown on markers of EMT following treatment with AA. Our results indicated that AA-induced EMT was associated with acquisition of fibroblast-like cell shape, loss of E-cadherin, and increases of alpha-SMA and collagen type I. Interestingly, exposure of HK-2 cells to 10μmol/L AA increased the mRNA and protein expression of gremlin in HK-2 cells. This increase was in parallel with a decrease in BMP-7 expression and a down-regulation of phosphorylated Smad1/5/8 protein levels. Moreover, transfection with siRNA to gremlin was able to recover BMP-7 signaling activity, and attenuate EMT-associated phenotypic changes induced by AA. Together, these observations strongly suggest that gremlin plays a critical role in the modulation of reno-protective action of BMP, and that inhibition of gremlin will be a promising means of developmenting novel treatments for AAN.

Inducing Dendritic Growth in Cultured Sympathetic Neurons

The shape of the dendritic arbor determines the total synaptic input a neuron can receive (1-3), and influences the types and distribution of these inputs (4-6). Altered patterns of dendritic growth and plasticity are associated with impaired neurobehavioral function in experimental models (7), and are thought to contribute to clinical symptoms observed in both neurodevelopmental disorders (8-10) and neurodegenerative diseases (11-13). Such observations underscore the functional importance of precisely regulating dendritic morphology, and suggest that identifying mechanisms that control dendritic growth will not only advance understanding of how neuronal connectivity is regulated during normal development, but may also provide insight on novel therapeutic strategies for diverse neurological diseases. Mechanistic studies of dendritic growth would be greatly facilitated by the availability of a model system that allows neurons to be experimentally switched from a state in which they do not extend dendrites to one in which they elaborate a dendritic arbor comparable to that of their in vivo counterparts. Primary cultures of sympathetic neurons dissociated from the superior cervical ganglia (SCG) of perinatal rodents provide such a model. When cultured in defined medium in the absence of serum and ganglionic glial cells, sympathetic neurons extend a single process which is axonal, and this unipolar state persists for weeks to months in culture (14,15). However, the addition of either bone morphogenetic protein-7 (BMP-7) (16,17) or Matrigel (18) to the culture medium triggers these neurons to extend multiple processes that meet the morphologic, biochemical and functional criteria for dendrites. Sympathetic neurons dissociated from the SCG of perinatal rodents and grown under defined conditions are a homogenous population of neurons (19) that respond uniformly to the dendrite-promoting activity of Matrigel, BMP-7 and other BMPs of the decapentaplegic (dpp) and 60A subfamilies (17,18,20,21). Importantly, Matrigel- and BMP-induced dendrite formation occurs in the absence of changes in cell survival or axonal growth (17,18). Here, we describe how to set up dissociated cultures of sympathetic neurons derived from the SCG of perinatal rats so that they are responsive to the selective dendrite-promoting activity of Matrigel or BMPs.

Activity of bone morphogenetic protein-7 after treatment at various temperatures: Freezing vs. pasteurization vs. allograft

Insufficient bone union is the occasional complication of biomechanical reconstruction after malignant bone tumor resection using temperature treated tumor bearing bone; freezing, pasteurization, and autoclaving. Since bone morphogenetic protein (BMP) plays an important role in bone formation, we assessed the amount and activity of BMP preserved after several temperature treatments, including −196 and −73°C for 20min, 60 and 100°C for 30min, 60°C for 10h following −80°C for 12h as an allograft model, and 4°C as the control. The material extracted from the human femoral bone was treated, and the amount of BMP-7 was analyzed using an enzyme-linked immunosorbent assay. Then, the activity of recombinant human BMP-7 after the treatment was assessed using a bioassay with NIH3T3 cells and immunoblotting analysis to measure the amount of phospho-Smad, one of the signaling substrates that reflect the intracellular reaction of BMPs. Both experiments revealed that BMP-7 was significantly better preserved in the hypothermia groups. The percentages of the amount of BMP-7 in which the control group was set at 100% were 114%, 108%, 70%, 49%, and 53% in the −196, −73, 60, 100°C, and the allograft-model group, respectively. The percentages of the amount of phospho-Smad were 89%, 87%, 24%, 4.9%, and 14% in the −196, −73, 60, 100°C, and the allograft-model group, respectively. These results suggested that freezing possibly preserves osteoinductive ability than hyperthermia treatment.

The antioxidative effect of bone morphogenetic protein-7 against high glucose-induced oxidative stress in mesangial cells

Bone morphogenetic protein-7 (BMP-7) protects kidneys from diabetic nephropathy (DN), and high glucose (HG)-induced oxidative stress is involved in DN. We investigated the antioxidative ability of BMP-7 using HG-treated mesangial cells. We treated rat mesangial cells (RMCs) with recombinant human BMP-7 (rhBMP-7) and examined changes in reactive oxygen species (ROS) levels and intracellular signals in response to HG-induced oxidative stress. rhBMP-7 decreased the level of ROS in HG-treated RMCs. In contrast, lowering endogenous BMP-7 by siRNA or BMP receptor II (BMP-RII) by anti-BMP-RII antibodies increased the level of ROS in HG-treated RMCs. rhBMP-7 increased Smad-1,5,8 phosphorylation, decreased PKCζ and c-Jun N-terminal kinase (JNK) phosphorylation, and decreased fibronectin and collagen IV synthesis in HG-treated RMCs. In conclusion, we found that BMP-7 could protect mesangial cells from HG-induced oxidative stress by activating BMP-RII. The antioxidative activity of BMP-7 was primarily due to inhibition of PKCζ, JNK phosphorylation, and c-jun activation.

BMP-7 fails to attenuate TGF- 1-induced epithelial-to-mesenchymal transition in human proximal tubule epithelial cells

In rodent models of chronic renal disease bone morphogenetic protein-7 (BMP-7) has been shown to halt disease progression and promote recovery. Subsequent studies utilizing immortalized rodent renal cell lines showed that BMP-7 was renoprotective by antagonizing TGF-beta1-stimulated epithelial-to-mesenchymal transition (EMT). The present study sought to determine if BMP-7 prevents TGF-beta1-induced EMT in primary (RPTEC) and immortalized (HK-2) human proximal tubule epithelial cells. EMT was determined by quantitative real-time PCR analysis of e-cadherin, vimentin, CTGF and TGF-beta1 transcript expression and immunocytochemical analysis of ZO-1 and alpha-smooth muscle actin (alpha-SMA) protein expression following TGF-beta1 treatment in RPTEC and HK-2 cells. In RPTEC and HK-2 cells, TGF-beta1 significantly reduced e-cadherin expression and significantly increased vimentin, CTGF and TGF-beta1 expression. TGF-beta1 also diminished ZO-1 immunoreactivity and increased alpha-SMA expression in confluent cell monolayers. Co-incubation of TGF-beta1 with an anti-TGF-beta1 neutralizing antibody substantially reduced the cytokine's effects, which indicated EMT in these cells was inhibitable. Co-administration of BMP-7 over a broad concentration range (0.01-100 microg/ml) with TGF-beta1 failed to attenuate EMT in RPTEC or HK-2 cells, as demonstrated by no inhibition of altered e-cadherin, vimentin, CTGF and TGF-beta1 expression and no restoration of ZO-1 immunoreactivity. Furthermore, when BMP-7 was applied to proximal tubule cells alone, it also decreased e-cadherin expression and increased vimentin, CTGF and TGF-beta1 expression. Additionally, BMP-7 failed to induce the mesenchymal-to-epithelial transition (MET) in NRK-49F rat renal fibroblasts. BMP-7 did however prevent TGF-beta1-mediated e-cadherin downregulation in TCMK-1 mouse renal tubular epithelial cells. BMP-7 activity was routinely confirmed by examining BMP-7-induced phosphorylation of SMADs 1/5/8, BMP-7 regulation of BMPR-IA, BMP-7-mediated reduction of IL-6 transcript expression and BMP-7-mediated reduction of secreted IL-6 and IL-8 proteins. In the present study, despite confirming BMP-7 regulation of receptor expression and induction of downstream signalling events, we were unable to demonstrate BMP-7 inhibition of EMT in either primary or immortalized human proximal tubule cells. Moreover, we were unable to demonstrate BMP-7-stimulated MET in rat renal fibroblasts. A protective effect was however observed at an elevated BMP-7 concentration in mouse renal tubular epithelial cells.

Strain imparted during impaction grafting may contribute to bony incorporation

In order to investigate the osteoinductive properties of allograft used in impaction grafting and the effect of strain during impaction on these properties, we designed an in vitro experiment to measure strain-related release of bone morphogenetic protein-7 (BMP-7) from fresh-frozen femoral head allograft. A total of 40 10 mm cubes of cancellous bone were cut from ten samples of fresh-frozen femoral head. The marrow was removed from the cubes and the baseline concentrations of BMP-7 were measured. Specimens from each femoral head were allocated to four groups and subjected to different compressive strains with a material testing machine, after which BMP-7 activity was reassessed. It was present in all groups. There was a linear increase of 102.1 pg/g (95% confidence interval 68.6 to 135.6) BMP-7 for each 10% increase in strain. At 80% strain the mean concentration of BMP-7 released (830.3 pg/g bone) was approximately four times that released at 20% strain. Activity of BMP-7 in fresh-frozen allograft has not previously been demonstrated. This study shows that the freezing and storage of femoral heads allows some maintenance of biological activity, and that impaction grafting provides a source of osteoinductive bone for remodelling. We have shown that BMP-7 is released from fresh-frozen femoral head cancellous bone in proportion to the strain applied to the bone. This suggests that the impaction process itself may contribute to the biological process of remodelling and bony incorporation.

Bone morphogenetic protein-7 (BMP7) in chronic kidney disease

Bone morphogenetic protein-7 (BMP7) is a member of the BMP-subfamily of perhaps a dozen proteins within the TGFbeta-superfamily of cysteine-knot fold cytokine-growth factors. BMP7 has pivotal functions during renal and eye development. In adult organisms, BMP7 is heavily expressed in kidney, specifically in podocytes, distal tubules and collecting ducts. The activity of BMP7 is reduced by inhibitors including some members of the dan-cerberus group and CTGF but can be enhanced by endoglin and KCP. Renal BMP7 disappears early in fibrogenic renal diseases which may facilitate progression. Exogenous administration of rhBMP7 or transgenic overexpression reduces renal fibrogenesis and apoptosis as well as transdifferentiation of epithelial cells. BMP7 improves maintenance of nephron function and structural integrity. These antifibrogenic activities result from inhibition of the nuclear translocation of TGFbeta-activated smad3 by smad6 downstream of BMP7-activated smad5. Although at present the beneficial effects of BMP7 have only been studied in rodent models of chronic renal diseases, there is promise for therapeutic utility of rhBMP7 or small molecule BMP7 agonists in patients.

BMP7 is a podocyte survival factor and rescues podocytes from diabetic injury

In early diabetic renal injury, there is podocyte drop-out (but no decrease in the number of other glomerular cells) which is thought to cause glomerular proteinuria and subsequent diabetic glomerular injury. We tested the hypothesis that early diabetic podocyte injury is caused, in part, by downregulation of bone morphogenetic protein-7 (BMP7) and loss of its autocrine function in murine podocytes. High glucose (HG; 25 mM) induces rounding of differentiated podocytes and changes in the distribution of F-actin but without quantitative changes in E-cadherin and the podocyte markers podocin, CD2AP, Neph1, or synaptopodin. HG reduces BMP7 secretion and activity but does not affect BMP receptor levels in murine podocytes. In these cells, BMP7 effectively activates smad5 (but not smad1) and raises p38 phosphorylation [which is also increased by transforming growth factor-beta (TGF-beta)]. HG as well as TGF-beta raise caspase-3 activity, increase apoptosis, and reduce cell survival which is, in part, blocked by BMP7. Knockdown and forced expression studies indicate that smad5 is required as well as sufficient for these actions of BMP7. These findings indicate that BMP7 is a differentiation and survival factor for podocytes, requires smad5, and can reduce diabetic podocyte injury.

Bone morphogenetic protein-7 expression and activity in the human adult normal kidney is predominently localized to the distal nephron

Bone morphogenetic protein-7 (BMP)-7 plays an important role during fetal kidney development. In the adult, BMP-7 is most strongly expressed in the kidney compared to other organs, but the exact expression pattern as well as the function of BMP-7 is unclear. The major aim of the present study was to define which parts of the human kidney do physiologically express BMP-7 and which cells appear to be targets of BMP activity by showing phosphorylated BMP-receptor-associated Smads 1, 5, or 8 and inhibitor of differentiation factor 1 (ID1) expression. BMP-7 expression was localized by immunohistology to the epithelia of the distal tubule as well as the collecting ducts (CDs). Phospho-Smads 1/5/8 and ID1 expression largely colocalized with BMP-7 and was also localized in the epithelia of the distal tubule and the CDs. This was confirmed by polymerase chain reaction-based mRNA expression analysis. In vitro, proximal tubular cells (PTCs) expressed BMP receptors and BMP-receptor-associated Smads and were reactive to BMP-7. Our data indicate that BMP-7 expression in the adult human kidney appears to be more restricted than in the fetal situation and predominantly found in the distal nephron. Also, evidence of in vivo BMP signalling (i.e. phospho-Smads and ID1 expression) was found there. These findings suggest that BMP-7 plays a physiological role mostly in this part of the kidney. Still, as reported previously, PTCs are responsive to BMP-7, but presumably not in an autocrine or paracrine mode in normal adult kidneys.

Loss of tubular bone morphogenetic protein-7 in diabetic nephropathy.

Bone morphogenetic protein-7 (BMP7), a member of the transforming growth factor-beta (TGF-beta) superfamily of cytokines, is highly expressed in renal tubules and generally promotes maintenance of epithelial phenotype. It was examined whether, during the evolution of experimental diabetic nephropathy, the renal expression of BMP7 and BMP7 receptors declines, and the hypothesis that loss of BMP7 activity is profibrogenic in proximal tubular cells was tested. Moreover, in vitro studies in cultured proximal tubular cells were performed to examine putative mechanisms that cause these changes. At 15 wk of streptozotocin-induced diabetes, renal expression of BMP7 is declined by about half, and it decreased further by 30 wk to <10% of timed controls. Renal expression of the high-affinity BMP type II receptor and the type I receptor Alk2 (activin receptor-like kinase-2) decreased. Alk3 tended to decrease, but Alk6 remained unchanged. During the evolution of diabetic nephropathy, the secreted BMP antagonist gremlin increased substantially. In cultured tubular cells, TGF-beta reduced BMP7 and Alk3 expression and increased gremlin but did not interrupt BMP7-induced activation of smad5 or Erk1 and -2. In contrast, BMP7 did not alter TGF-beta expression. Neutralization of endogenous BMP7 in cultured proximal tubular cells raised the expression of fibronectin and tended to increase collagen alpha(1) III mRNA levels. In conclusion, in experimental diabetic nephropathy, renal tubular BMP7 and some of its receptors decreased and gremlin, a secreted BMP antagonist, increased. Some, but not all, of these changes are explained by increased TGF-beta. The loss of BMP7 activity per se is profibrogenic in tubular cells.

Molecular and cellular analysis of embryonic avian tongue development.

Signalling cascades first described in Drosophila have been found to regulate patterning and outgrowth in a number of structures in higher vertebrates. We sought to determine whether the evolutionarily conserved genes were important during the development of the tongue. In situ hybridisation was used to determine the temporo-spatial expression of a panel of conserved genes. Histological examination and incorporation of BrdU were used to determine the mechanism by which the tongue develops. We show that evolutionarily conserved genes were expressed in distinct dynamic patterns during tongue development. Sonic Hedgehog (Shh) and Patched (Ptc) were found only in the dorsal tongue epithelium. Shh expression was only observed in the suprabasal layers, whereas Ptc was observed in both basal and suprabasal layers. Cell division in the epithelium was concentrated in regions devoid of Shh. Expression of bone morphogenetic protein-7 (BMP) was identical to that of Shh. Shh and Ptc expression were never detected in the mesenchyme. Ectopic expression of Noggin (a potent antagonist of the BMPs) caused severe abnormalities in tongue morphology, including swelling of the mesenchymal component and a thickening of the epithelial layer. Data from this study suggests that the epithelium and mesenchyme express quite different genes during development. However BMP activity acts to inhibit growth in both tissues.