Non-human Primate Papio Ursinus Research Articles

Developmental pathways of periodontal tissue regeneration: Developmental diversities of tooth morphogenesis do also map capacity of periodontal tissue regeneration?

Nothing is known on the impact of developmental divergence on periodontal tissue regeneration in vertebrate animals. Molecularly, the induction of tooth morphogenesis is highly conserved deploying across animal phyla a constant and reproducible set of gene pathways, which result in morphogenesis of multiple odontode forms and shapes. Genetic mutations positively affect animal speciation via evolving biting and masticatory forces as well as dietary habits selectively imprinted in animal phyla during evolutionary speciation. The geometry of the attachment apparatus of a tooth is important for the interpretation of the induction of cementogenesis with de novo Sharpey's fibres as in thecodonty, ie, a tripartite attachment of alveolar bone, periodontal ligament and cementum. This review addresses the tooth implantation in different animal clades from the fibrous attachment of the Elasmobranch Carcharinus obscurus dusky shark, reviewing the evolution and functional significance of cementum with functionally inserted Sharpey's fibres. In sharks there is a continuous tooth replacement mechanistically supported by the continuously erupting dental lamina. We show that the arching of the continuously erupting dental lamina, a critical step for the selachians' tooth differentiation, is prominently characterized by transforming growth factor-β3 (TGF-β3 ) expression not only within the dental lamina but also in cellular condensations in the mesenchymal tissues of the erupting tooth. Such findings indicate the pleiotropic multifaceted activity of a highly conserved mammalian gene across genera, masterminding tooth morphogenesis in both selachians and mammals as well as periodontal tissue induction in the non-human primate Papio ursinus. In P.ursinus, the induction of cementogenesis entails the expression of TGF-β3 and osteocalcin with fine-tuning and regulation of bone morphogenetic proteins BMP-2 and BMP-7, and upregulation of TGF-β3 . TGF-β3 autoinduction and upregulation during the induction of cementogenesis and osteogenesis in P.ursinus provide novel insights into the induction of cementogenesis. It is hypothesized that the evolutionary expression and upregulation of the TGF-β3 gene may provide the mechanistic insights into the induction of extensive cementogenesis as seen in stem mammals and the induction of trabecular-like cementum formation in mosasaurs' tooth attachment. Aspidin, the precursor of cementum, was reported to appear 310-330million years ago (Ma) in Odontostraci armoured fish. Studies showed that the differentiation of cementum with inserted Sharpey's fibres is also present in lower amniotes such as Diatectomorpha or Diadectidae, the first herbivorous tetrapods, 323Ma. In mosasaurs, 168-165Ma, there is the induction of extensive trabeculation of cementum though nothing is known on the phylogenetic temporo-spatial evolution of cementum before Diadectidae and stem mammals. The large trabeculations of cementum as seen in the attachment of extinct mosasaurs invocates a pleiotropic capacity of cemental growth previously unknown. The appearance of cementum facing a vascularized and innervated periodontal ligament space with Sharpey's fibres inserting on to mineralized cementum provides a multiform pleiotropic masticatory apparatus adapted to multiple biting and lacerating forces as well as finely tuned and controlled forces beyond mastication and deglutition. The remarkable cementogenesis as seen in stem mammals but particularly in mosasaurs with cemental trabeculations across the ligament space invocates the developmental capacity of cementum. The large cemental trabeculations as seen in mosasaurs and the cemental growth in stem mammals, together with regenerating scenarios in P.ursinus with large seams of cellular cementum and cementoid populated by contiguous cementoblasts indicate the continuous molecular cross-talk between cementum, newly formed cementoid matrix, cementoblasts and extracellular matrix soluble molecular signals. This molecular cross-talk may control the biomolecular homeostasis of both cementum and periodontal ligament, including angiogenesis. A further molecular scenario is invocated by the tight and exquisite anatomical relationships between the cementoid surfaces and the newly formed capillaries. The primitiveness of the craniate masticatory mineralized craniofacial apparatus has been controlled by several yet ancestral common genes not lastly the TGF-β3 gene. The TGF-β3 might have been responsible for the induction of cementogenesis not only in extant P.ursinus but also in Diatectomorpha and mosasaurs, thus providing continuous evolutionary mechanisms for the induction of tissue morphogenesis across animal phyla for almost a billion years of evolution, epitomizing Nature's parsimony in controlling tissue induction and morphogenesis. TGF-β receptor II regulates osterix expression via Smad-dependent pathways indicating that TGF-β signalling acts as an upstream regulator of osterix during cementoblast differentiation. The presence of morphogenetic signals within the cemental matrix capable of inducing bone formation needs now to be assigned: bone induction initiated by extracted and partially purified cemental matrices may be the result of a slow release of embryonic remnants of osteogenic signals required and deployed during cementogenesis. The cementum may thus rule the periodontal ligament space homeostasis, remodelling and repair by releasing sequestered morphogenetic signals that were deployed during embryogenesis.

Redundancy and Molecular Evolution: The Rapid Induction of Bone Formation by the Mammalian Transforming Growth Factor-β3 Isoform.

The soluble osteogenic molecular signals of the transforming growth factor-β (TGF-β) supergene family are the molecular bases of the induction of bone formation and postnatal bone tissue morphogenesis with translation into clinical contexts. The mammalian TGF-β3 isoform, a pleiotropic member of the family, controls a vast array of biological processes including the induction of bone formation. Recombinant hTGF-β3 induces substantial bone formation when implanted with either collagenous bone matrices or coral-derived macroporous bioreactors in the rectus abdominis muscle of the non-human primate Papio ursinus. In marked contrast, the three mammalian TGF-βs do not initiate the induction of bone formation in rodents and lagomorphs. The induction of bone by hTGF-β3/preloaded bioreactors is orchestrated by inducing fibrin-fibronectin rings that structurally organize tissue patterning and morphogenesis within the macroporous spaces. Induced advancing extracellular matrix rings provide the structural anchorage for hyper chromatic cells, interpreted as differentiating osteoblasts re-programmed by hTGF-β3 from invading myoblastic and/or pericytic differentiated cells. Runx2 and Osteocalcin expression are significantly up-regulated correlating to multiple invading cells differentiating into the osteoblastic phenotype. Bioreactors pre-loaded with recombinant human Noggin (hNoggin), a BMPs antagonist, show down-regulation of BMP-2 and other profiled osteogenic proteins' genes resulting in minimal bone formation. Coral-derived macroporous constructs preloaded with binary applications of hTGF-β3 and hNoggin also show down-regulation of BMP-2 with the induction of limited bone formation. The induction of bone formation by hTGF-β3 is via the BMPs pathway and it is thus blocked by hNoggin. Our systematic studies in P. ursinus with translational hTGF-β3 in large cranio-mandibulo-facial defects in humans are now requesting the re-evaluation of “Bone: formation by autoinduction” in primate models including humans.

Tissue segregation restores the induction of bone formation by the mammalian transforming growth factor-β3 in calvarial defects of the non-human primate Papio ursinus

A diffusion molecular hypothesis from the dura and/or the leptomeninges below that would control the induction of calvarial membranous bone formation by the recombinant human transforming growth factor-β3 (hTGF-β3) was investigated. Coral-derived calcium carbonate-based macroporous constructs (25 mm diameter; 3.5/4 mm thickness) with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) were inserted into forty calvarial defects created in 10 adult Chacma baboons Papio ursinus. In 20 defects, an impermeable nylon foil membrane (SupraFOIL®) was inserted between the cut endocranial bone and the underlying dura mater. Twenty of the macroporous constructs were preloaded with hTGF-β3 (125 μg in 1000 μl 20 mM sodium succinate, 4% mannitol pH4.0), 10 of which were implanted into defects segregated by the SupraFOIL® membrane, and 10 into non-segregated defects. Tissues were harvested on day 90, processed for decalcified and undecalcified histology and quantitative real-time polymerase chain reaction (qRT-PCR). Segregated untreated macroporous specimens showed a reduction of bone formation across the macroporous spaces compared to non-segregated constructs. qRT-PCR of segregated untreated specimens showed down regulation of osteogenic protein-1 (OP-1), osteocalcin (OC), bone morphogenetic protein-2 (BMP-2), RUNX-2 and inhibitor of DNA binding-2 and -3 (ID2,ID3) and up regulation of TGF-β3, a molecular signalling pathway inhibiting the induction of membranous bone formation. Non-segregated hTGF-β3/treated constructs also showed non-osteogenic expression profiles when compared to non-segregated untreated specimens. Segregated hTGF-β3/treated 7% HA/CC constructs showed significantly greater induction of bone formation across the macroporous spaces and, compared to non-segregated hTGF-β3/treated constructs, showed up regulation of OP-1, OC, BMP-2, RUNX-2, ID2 and ID3. Similar up-regulated expression profiles were seen for untreated non-segregated constructs. TGF-β signalling via ID genes creates permissive or refractory micro-environments that regulate the induction of calvarial bone formation which is controlled by the exogenous hTGF-β3 upon segregation of the calvarial defects. The dura is the common regulator of the induction of calvarial bone formation modulated by the presence or absence of the SupraFOIL® membrane with or without hTGF-β3.

Synergistic induction of bone formation by hOP-1, hTGF-β3 and inhibition by zoledronate in macroporous coral-derived hydroxyapatites

Thirty coral-derived calcium carbonate-based macroporous constructs with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) were implanted in the rectus abdominis of three adult non-human primate Papio ursinus to investigate the intrinsic induction of bone formation. Macroporous constructs with 125μg human recombinant osteogenic protein-1 (hOP-1) or 125μg human recombinant transforming growth factor-β3 (hTGF-β3) were also implanted. The potential synergistic interaction between morphogens was tested by implanting binary applications of hOP-1 and hTGF-β3 5:1 by weight, respectively. To evaluate the role of osteoclastic activity on the implanted macroporous surfaces, coral-derived constructs were pre-loaded with 0.24mg of bisphosphonate zoledronate (Zometa®). To correlate the morphology of tissue induction with osteogenic gene expression and activation, harvested specimens on day 90 were analyzed for changes in OP-1 and TGF-β3 mRNA synthesis by quantitative real-time polymerase chain reaction (qRT-PCR). The induction of bone formation in 7% HA/CC solo correlated with OP-1 expression. Massive bone induction formed by binary applications of the recombinant morphogens. Single applications of hOP-1 and hTGF-β3 also resulted in substantial bone formation, not comparable however to synergistic binary applications. Zoledronate-treated macroporous constructs showed limited bone formation and in two specimens bone formation was altogether absent; qRT-PCR showed a prominent reduction of OP-1 gene expression whilst TGF-β3 expression was far greater than OP-1. The lack of bone formation by zoledronate-treated specimens indicates that osteoclastic activity on the implanted coral-derived constructs is critical for the spontaneous induction of bone formation. Indirectly, zoledronate-treated samples showing lack of OP-1gene expression and absent or very limited bone formation by induction confirm that the spontaneous induction of bone formation by coral-derived macroporous constructs is initiated by secreted BMPs/OPs, in context the OP-1 isoform.

Induction of bone formation by transforming growth factor‐β2 in the non‐human primate Papio ursinus and its modulation by skeletal muscle responding stem cells

Four adult non-human primates Papio ursinus were used to study induction of bone formation by recombinant human transforming growth factor-beta(2) (hTGF-beta(2)) together with muscle-derived stem cells. The hTGF-beta(2) was implanted in rectus abdominis muscles and in calvarial defects with and without addition of morcellized fragments of striated muscle, harvested from the rectus abdominis or temporalis muscles. Expression of osteogenic markers including osteogenic protein-1, bone morphogenetic protein-3 and type IV collagen mRNAs from generated specimens was examined by Northern blot analysis. Heterotopic intramuscular implantation of 5 and 25 microg hTGF-beta(2) combined with 100 mg of insoluble collagenous bone matrix yielded large corticalized mineralized ossicles by day 30 with remodelling and induction of haematopoietic marrow by day 90. Addition of morcellized rectus abdominis muscle to calvarial implants enhanced induction of bone formation significantly by day 90. In Papio ursinus, in marked contrast to rodents and lagomorphs, hTGF-beta(2) induced large corticalized and vascularized ossicles by day 30 after implantation into the rectus abdominis muscle. This striated muscle contains responding stem cells that enhance the bone induction cascade of hTGF-beta(2). Induction of bone formation by hTGF-beta(2) in the non-human primate Papio ursinus may occur as a result of expression of bone morphogenetic proteins on heterotopic implantation of hTGF-beta(2); the bone induction cascade initiated by mammalian TGF-beta proteins in Papio ursinus needs to be re-evaluated for novel molecular therapeutics for induction of bone formation in clinical contexts.

Soluble and insoluble signals sculpt osteogenesis in angiogenesis.

The basic tissue engineering paradigm is tissue induction and morphogenesis by combinatorial molecular protocols whereby soluble molecular signals are combined with insoluble signals or substrata. The insoluble signal acts as a three-dimensional scaffold for the initiation of de novo tissue induction and morphogenesis. The osteogenic soluble molecular signals of the transforming growth factor-β (TGF-β) supergene family, the bone morphogenetic/osteogenic proteins (BMPs/OPs) and, uniquely in the non-human primate Papio ursinus (P. ursinus), the three mammalian TGF-β isoforms induce bone formation as a recapitulation of embryonic development. In this paper, I discuss the pleiotropic activity of the BMPs/OPs in the non-human primate P. ursinus, the induction of bone by transitional uroepithelium, and the apparent redundancy of molecular signals initiating bone formation by induction including the three mammalian TGF-β isoforms. Amongst all mammals tested so far, the three mammalian TGF-β isoforms induce endochondral bone formation in the non-human primate P. ursinus only. Bone tissue engineering starts by erecting scaffolds of biomimetic biomaterial matrices that mimic the supramolecular assembly of the extracellular matrix of bone. The molecular scaffolding lies at the hearth of all tissue engineering strategies including the induction of bone formation. The novel concept of tissue engineering is the generation of newly formed bone by the implantation of "smart" intelligent biomimetic matrices that per se initiate the ripple-like cascade of bone differentiation by induction without exogenously applied BMPs/OPs of the TGF-β supergene family. A comprehensive digital iconographic material presents the modified tissue engineering paradigm whereby the induction of bone formation is initiated by intelligent smart biomimetic matrices that per se initiate the induction of bone formation without the exogenous application of the soluble osteogenic molecular signals. The driving force of the intrinsic induction of bone formation by bioactive biomimetic matrices is the shape of the implanted substratum. The language of shape is the language of geometry; the language of geometry is the language of a sequence of repetitive concavities, which biomimetizes the remodelling cycle of the primate osteonic bone.

Transforming Growth Factor-β Isoforms and the Induction of Bone Formation

Craniofacial skeletal reconstruction remains a challenging problem despite major molecular and surgical developments in the understanding of bone formation by induction. The induction of bone formation has been a critical topic of research across the planet. The bone induction principle identified important cues for tissue engineering of bone, namely, osteogenic soluble molecular signals, the bone morphogenetic and osteogenic proteins, and insoluble signals or substrata including biomimetic bioactive matrices and responding stem cells. In primates, and in primates only, the osteogenic soluble molecular signals that initiate the induction of bone formation additionally include the 3 mammalian transforming growth factor-beta (TGF-beta) isoforms, members of the TGF-beta supergene family. The mammalian TGF-beta isoforms, when implanted in the rectus abdominis muscle of the nonhuman primate Papio ursinus, induce rapid and substantial endochondral bone formation resulting in large corticalized ossicles by day 30 after heterotopic implantation; in calvarial defects of the same nonhuman primates, identical or higher doses of the TGF-beta protein do not induce bone formation because of the overexpression of Smad-6 and Smad-7, gene product inhibitors of the TGF-beta signaling pathway. The addition of minced fragments of autogenous rectus abdominis muscle partially restores the osteoinductive activity of the human TGF-beta3 isoform resulting in the induction of bone formation in the treated calvarial defects. Recombinant human TGF-beta3 delivered by Matrigel matrix and implanted in class II and III furcation defects of mandibular molars of P. ursinus induce periodontal tissue regeneration. The addition of minced fragments of autogenous rectus abdominis muscle significantly enhances cementogenesis. This review highlights the induction of bone formation by the osteogenic proteins of the TGF-beta superfamily in the nonhuman primate P. ursinus and reviews combinatorial applications of myoblastic/myogenic stem cell-based therapeutics for bone induction and morphogenesis. The recruitment of myoendothelial cells is also discussed in the light of the intrinsic and spontaneous induction of bone formation by smart biomaterial matrices that induce bone differentiation in heterotopic extraskeletal sites of P. ursinus without the exogenous application of the osteogenic soluble molecular signals of the TGF-beta superfamily.

Immediate Loading of Modified Acid Etched Dental Implants in Postextraction Sockets: A Histological and Histomorphometrical Comparative Study in Nonhuman Primate Papio Ursinus

Immediate loading of dental implants inserted into fresh postextraction sites has recently been proposed as a novel but challenging surgical approach. However, histological evidence and comparative data are still missing. The aim of this study was an histological and histomorphometrical comparison of submerged and immediately loaded dental implants with a new modified acid etched surface inserted into postextraction sites of nonhuman primates. Thirty-two implants were placed in postextraction sockets of 4 adult Chacma Baboons (papio ursinus). Each baboon received 8 implants: 4 submerged and 4 immediately loaded. The implants were retrieved after 90 days of healing with a 4-mm trephine bur and processed for histology and histomorphometry. The bone-to-implant contact percentage in the submerged and immediate loaded implants was 86.02% and 86.85%, respectively, with no statistically significant differences. In the immediately loaded implants a greater amount of ongoing remodeling was observed. Immediate loading seemed to be a valid alternative to conventional technique when a implant is inserted into postextraction sockets. Further comparative studies on a greater number of samples are necessary to confirm our findings.

Cementogenesis and the induction of periodontal tissue regeneration by the osteogenic proteins of the transforming growth factor‐β superfamily

The antiquity and severity of periodontal diseases are demonstrated by the hard evidence of alveolar bone loss in gnathic remains of the Pliocene/Pleistocene deposits of the Bloubank Valley at Sterkfontein, Swartkrans and Kromdrai in South Africa. Extant Homo has characterized and cloned a superfamily of proteins which include the bone morphogenetic proteins that regulate tooth morphogenesis at different stages of development as temporally and spatially connected events. The induction of cementogenesis, periodontal ligament and alveolar bone regeneration are regulated by the co-ordinated expression of bone morphogenetic proteins. Naturally derived and recombinant human bone morphogenetic proteins induce periodontal tissue regeneration in mammals. Morphological analyses on undecalcified sections cut at 3-6 mum on a series of mandibular molar Class II and III furcation defects induced in the non-human primate Papio ursinus show the induction of cementogenesis. Sharpey's fibers nucleate as a series of composite collagen bundles within the cementoid matrix in close relation to embedded cementocytes. Osteogenic protein-1 and bone morphogenetic protein-2 possess a structure-activity profile, as shown by the morphology of tissue regeneration, preferentially cementogenic and osteogenic, respectively. In Papio ursinus, transforming growth factor-beta(3) also induces cementogenesis, with Sharpey's fibers inserting into newly formed alveolar bone. Capillary sprouting and invasion determine the sequential insertion and alignment of individual collagenic bundles. The addition of responding stem cells prepared by finely mincing fragments of autogenous rectus abdominis muscle significantly enhances the induction of periodontal tissue regeneration when combined with transforming growth factor-beta(3) implanted in Class II and III furcation defects of Papio ursinus.

The induction of bone formation by coral-derived calcium carbonate/hydroxyapatite constructs

The spontaneous induction of bone formation in heterotopic rectus abdominis and orthotopic calvarial sites by coral-derived biomimetic matrices of different chemical compositions was investigated in a long-term study in the non-human primate Papio ursinus. Coral-derived calcium carbonate constructs were converted to hydroxyapatite by hydrothermal exchange. Limited conversion produced hydroxyapatite/calcium carbonate (HA/CC) constructs of 5% and 13% hydroxyapatite. Rods of 20 mm in length and 7 mm in diameter were implanted in heterotopic rectus abdominis sites; discs 25 mm in diameter were implanted in orthotopic calvarial defects of six adult non-human primates P. ursinus. Heterotopic samples also included fully converted hydroxyapatite replicas sintered at 1100 °C. To further enhance spontaneous osteoinductive activity, fully converted hydroxyapatite replicas were coated with the synthetic peptide P15 known to increase the adhesion of fibroblasts to anorganic bovine mineral. Bone induction was assessed at 60, 90 and 365 days by histological examination, alkaline phosphatase and osteocalcin expression, as well as by the expression of BMP-7, GDF-10 and collagen type IV mRNAs. Induction of bone occurred in the concavities of the matrices at all time points. At 365 days, bone marrow was evident in the P15-coated and uncoated implants. Resorption of partially converted calcium carbonate/hydroxyapatite was apparent, as well as remodeling of the newly formed bone. Northern blot analyses of samples from heterotopic specimens showed high levels of expression of BMP-7 and collagen type IV mRNA in all specimen types at 60 days, correlating with the induction of the osteoblastic phenotype in invading fibrovascular cells. Orthotopic specimens showed prominent bone formation across the different implanted constructs. The concavities of the matrices biomimetize the remodeling cycle of the osteonic primate cortico-cancellous bone and promote the ripple-like cascade of the induction of bone formation. This study demonstrates for the first time that partially converted HA/CC constructs also induce spontaneous differentiation of bone, albeit only seen one year post-implantation.

Biomimetic Smart Hydroxyapatite/Biphasic Tricalcium Phosphate Biomatrices Induce Bone Formation

Long-term studies in the non-human primate Papio ursinus were set to investigate the induction of bone formation in biphasic hydroxyapatite tricalcium phosphate (HA/TCP) biomimetic matrices, 20/80 and 40/60, respectively. Biomimetic matrices were implanted in the rectus abdominis and in calvarial defects of 4 adult Papio ursinus. Morphological analyses on day 90 and 365 showed significant induction of bone formation within concavities of the biomimetic matrices implanted in both heterotopic and orthotopic sites with resorption of the implanted biomimetic matrices. The smart biomimetic matrices induced de novo bone formation even in the absence of exogenously applied osteogenic proteins of the transforming growth factor-β superfamily.

The induction of endochondral bone formation by transforming growth factor-?3: Experimental studies in the non-human primate Papio ursinus

The induction of endochondral bone formation by transforming growth factor-?₃: Experimental studies in the non-human primate Papio ursinus

Bone loss in the ovariectomized baboonPapio ursinus: densitometry, histomorphometry and biochemistry

To develop a non-human primate model of systemic bone loss after ovariectomy, 24 ovariectomized (OVX) and eight control (non-OVX) female baboons Papio ursinus were investigated over a period of 48 months using bone mineral density (BMD), iliac crest bone histomorphometry, bone turnover markers, and variables of calcium metabolism. Lumbar spine (L1–L4) BMD measured by dual energy X-ray absorptiometry (DXA) decreased in OVX animals in the first 12 months (−7.6%) and showed a slow trend towards recovery after 24 months. Controls showed a slow increase in spinal BMD over 4 years (+9.7%). Total hip BMD decreased slowly up to 48 months in all animals (OVX −12.6%versus controls −10%); this indicated that OVX had a limited effect on total hip BMD. Forearm BMD did not change. The significant decrease in trabecular bone volume (TBV) of the iliac crest from baseline to 12 months was followed by some recovery. Microarchitectural deterioration of trabecular bone in OVX animals was demonstrated by a decline in trabecular number and an increase in trabecular spacing. These changes were also evident on sections of whole vertebrae, proximal femora and iliac crests. Changes in iliac TBV reflected spinal but not hip BMD changes in the OVX animals. Static and dynamic histomorphometric variables indicated that bone turnover was increased for 36 months following OVX. Controls showed no changes in histomorphometric variables. Bone specific alkaline phosphatase (ALPs) in OVX animals remained elevated throughout the study; osteocalcin (OC) was significantly elevated only at 6 and 12 months, and deoxypyridinoline (Pyr-D) was elevated at 12 months but declined after 24 months. ALPs was thus more sensitive to the long-term effects of OVX than were OC or Pyr-D. Controls showed no changes in bone turnover markers. This study showed consistent deleterious changes in lumbar BMD, bone histomorphometry with microarchitectural deterioration together with altered biochemical markers of bone turnover in the first 12 months after OVX. Since these changes resemble those in post-menopausal women, the non-human primate Papio ursinus is suitable for the study of bone loss in post-menopausal women.

Recapitulating Development: A Template for Periodontal Tissue Engineering

The induction of bone formation by the soluble osteogenic molecular signals of the transforming growth factor-beta (TGF-β) superfamily is a critical issue to periodontologists, molecular biologists, and tissue engineers alike, because preclinical studies in primates and clinical trials have demonstrated the bone induction capacity of bone morphogenetic and osteogenic proteins (BMPs/OPs) in clinical context. BMPs/OPs, pleiotropic members of the TGF-β superfamily, induce de novo endochondral bone formation as a recapitulation of embryonic development and act as soluble signals for tissue morphogenesis sculpting the multicellular mineralized structures of the periodontal tissues with functionally oriented periodontal ligament fibers inserting into newly formed cementum. This paper reviews the induction of the complex tissue morphologies of the periodontal tissues in the nonhuman primate Papio ursinus with furcation defects treated with doses of naturally derived and recombinantly produced human BMPs/OPs. Periodontal tissue regeneration develops as a mosaic structure in which the OPs of the TGF-β superfamily singly, synergistically, and synchronously initiate and maintain tissue induction and morphogenesis.

Recapitulating Development: A Template for Periodontal Tissue Engineering

The induction of bone formation by the soluble osteogenic molecular signals of the transforming growth factor-beta (TGF-beta) superfamily is a critical issue to periodontologists, molecular biologists, and tissue engineers alike, because preclinical studies in primates and clinical trials have demonstrated the bone induction capacity of bone morphogenetic and osteogenic proteins (BMPs/OPs) in clinical context. BMPs/OPs, pleiotropic members of the TGF-beta superfamily, induce de novo endochondral bone formation as a recapitulation of embryonic development and act as soluble signals for tissue morphogenesis sculpting the multicellular mineralized structures of the periodontal tissues with functionally oriented periodontal ligament fibers inserting into newly formed cementum. This paper reviews the induction of the complex tissue morphologies of the periodontal tissues in the nonhuman primate Papio ursinus with furcation defects treated with doses of naturally derived and recombinantly produced human BMPs/OPs. Periodontal tissue regeneration develops as a mosaic structure in which the OPs of the TGF-beta superfamily singly, synergistically, and synchronously initiate and maintain tissue induction and morphogenesis.

Bone morphogenetic proteins in craniofacial and periodontal tissue engineering: Experimental studies in the non-human primate Papio ursinus

The bone morphogenetic and osteogenic proteins (BMPs/OPs), pleiotropic members of the transforming growth factor-β (TGF-β) supergene family act as soluble signals for the de novo initiation of bone formation, sculpting the multicellular mineralized structures of the bone–bone marrow organ. The strikingly pleiotropic effects of BMPs/OPs spring from amino acid sequence variations in the carboxy-terminal domain and in the transduction of distinct signalling pathways by individual Smad proteins after transmembrane serine/threonine kinase complexes of type I and II receptors. BMPs/OPs are the common molecular initiators deployed for embryonic development and the induction of bone formation and regeneration in postnatal osteogenesis. Naturally derived BMPs/OPs extracted and purified from baboon and bovine bone matrices induce complete regeneration of non-healing calvarial defects in the non-human primate Papio ursinus as well as the induction of cementogenesis and the morphogenesis of a periodontal ligament system with a faithful insertion of Sharpey's fibers into the newly formed cementum. γ-Irradiated recombinant human osteogenic protein-1 (hOP-1) delivered by xenogeneic bovine collagenous bone matrices completely regenerated and maintained the architecture of the induced bone after treatment of calvarial defects with single applications of doses of 0.1, 0.5 and 2.5 mg hOP-1 per gram of carrier matrix. The long-term implantation of hOP-1 delivered by γ-irradiated bovine bone matrices induced the regeneration of the three essential components of the periodontium, i.e. cementum, periodontal ligament and alveolar bone. The osteogenic proteins of the TGF-β superfamily are sculpting tissue constructs that engineer skeletal tissue regeneration in molecular terms. The pleiotropy of the signalling molecules of the TGF-β superfamily is highlighted by the redundancy of molecular signals initiating bone formation, including the TGF-β isoforms per se, powerful inducers of endochondral bone formation but in the primate only. The induction of bone develops a mosaic structure in which members of the TGF-β superfamily singly, synergistically and synchronously initiate and maintain tissue induction and morphogenesis.