Dr Jean Elizabeth Aaron
- Position: Visiting Lecturer (Unpaid
- Areas of expertise: hard tissue histology; computer-assisted histomorphometry; undecalcified bone cryomicrotomy; transmission and scanning electron microscopy; cultured bone cells and models; bone microsphere harvesting
- Email: J.E.Aaron@leeds.ac.uk
- Location: 6.56a Garstang
After work experience at the Tropical Products Institute (London) and the Dairy Research Institute (Reading) I graduated in applied biology (University of Bradford).
I joined the flagship MRC Mineral Metabolism Unit (bone diseases), Leeds General Infirmary, and began a career in bone microscopy.
There followed my placement in France where I learned the latest methods in hard tissue microtomy and histomorphometry with pioneer P. Meunier (Lyons) with whom I also wrote my first paper (bone marrow adipose proliferation and haematopoietic cell decline in osteopoenia). At this time undecalcified bone preparation was especially challenging compared to soft tissues.
[Meunier, P., Aaron, J.E.,Edouard, C., Vignon, G.: Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. Clin Orthop Rel Res 80:147-54: 1971.]
Back in Leeds my newly equipped bone research laboratory provided both a routine iliac crest biopsy service with technical assistance (M. Nicholson) and a basis for innovative substructural specialisation encouraged by H.M. Frost (Director of Orthopaedic Surgery, Henry Ford Hospital, Detroit), the "father" of current bone remodelling concepts.
My bone biology laboratory was unique in spanning the structural spectrum from the microarchitectural to the macromolecular level and generated novel information for my PhD thesis (University of Leeds, 1974; "The Development of the Bone Cell and its Role in Mineralization and Resorption") with MRC support and with F.G.E. Pautard and B.E.C. Nordin as distinguished mentors. This provided the foundation for my future research programme.
A key debut lecture in Vienna (at a time when women speakers were rare) introduced me to the conference circuit of learned societies (e.g. European Symposium on Calcified Tissues; International Bone and Mineral Symposium; together with the national Bone and Tooth Society and the British Society for Developmental Biology).
There followed funded invitations to speak at prestigious workshops (e.g. Sun Valley, Idaho; Copenhagen, Aarhus). Also were sessions as Chair, tutorial presentations at two British Council Courses and a role at York in organising the first poster session ever held at a major bone meeting (now an established format).
Within the Leeds MRC Unit my histomorphometric output on clinical bone biopsies and NHS autopsy control specimens complemented the biochemical, endocrinological and densitometric data of colleagues, facilitated by a technical team (Kathryn, Tom, L.Cattley, C. Brain, with two graduates registered for higher degrees, D.H. Carter, N.B. Makins). At the same time, my independent research mapped the calcification status of osteocyte populations in intact murine calvarium leading to the significant discovery of an intracellular loading and unloading cycle, contrary to the prevailing view of extracellular epitaxy on collagen fibres.
Scientists from across the globe were frequent guests, resulting in staff exchanges and my guidance in establishing similar laboratories in Zagreb and Malmo. Long-term visiting scientists from the former Yugoslavia (D. Dekanic), from Poland (L. Stasiak) and India (K.Sagreiya) constituted a valuable research asset together with others from Israel, Egypt, Norway, and Spain for shorter periods. Lasting bonds were formed from these exchanges, including the privilege of presenting a Memorial Lecture in tribute to an eminent Dutch skeletal scientist (J. Birkenhager of Rotterdam).
Following closure of the Mineral Metabolism Unit with retirement of its Director, B.E.C. Nordin, I was awarded continued MRC funding for my laboratory and an appointment as MRC Visiting Fellow at the University of Leeds, with accomodation provided by successive Heads of Anatomy (J. Moore, D.R. Johnson) and with 2 PhD students under my supervision on Anatomy Scholarships (K.M. Linton, V. Fallon).
The University arrangement also facilitated a continued collaboration with A.D. Care (Head of Animal Physiology and Nutrition) investigating maternal/foetal mineral exchange, together with a novel study of the trabecular regeneration mechanism with veterinarian T.M. Skerry (Comparative Orthopaedic Research Unit, University of Bristol), both projects centred on an ovine model.
[Aaron, J.E., Abbas, S.K., Colwell, A., Eastell, R., Oakley, B.A., Russell, R.G.G., Care, A.D] Parathyroid gland hormones in the skeletal development of the ovine foetus. Bone & Min 16:121-29:1992]
At the behest of the MRC was a direct association with clinician J.A. Kanis and his WHO Bone Disease Collaborating Centre (University of Sheffield). From this arose an association with leading scientist G. Rodan (Merck, Sharpe, Dohme Laboratories, Pennsylvania) and acccess to unique vertebral material exposed to a frontline bisphosphonate therapy for histomorphometric investigation of bone loss prevention.
The arrival of various archeological specimens were an unusual diversion, including the earliest recorded incidence of Paget's disease with osteocytes in a remarkable state of preservation; at the same time were neonate calvaria suspected of leprosy from a castle burial ground in Ireland which served to illustrate the lytic effects of terrestrial fungi.
It was a bonus when my former MPhil student (D.H.Carter) returned to a PhD thesis under my supervision, at the same time fulfilling his new post with M. Ferguson and P. Sloan (Turner Dental Institute, University of Manchester).
The partnership between the two of us was instrumental in "cutting edge" immunohistochemical mapping that became a "game changer" with the arrival of monoclonal antibody markers of collagenous (particularly types III and IV) and noncollagenous proteins (osteocalcin, osteopontin, sialoprotein, fibronectin, tenascin).
In turn this opened postgraduate opportunities for a Leeds dental staff member (F. Luther; on Sharpey fibre atrophy after ovariectomy), an Iranian veterinarian (S.M. Shahtaheri; on the effect of pregnancy and lactation on cancellous microarchitecture) and a Jordanian dentist (A. Al-Qtaitat; on periosteal Sharpey fibre calcification with age), with projects that also benefitted from the proximity to SEM/EDX technology (R.C. Shore, Oral Biology, Leeds Dental Institute) and FEGSEM/ slam freezing (P.Hatton, Sheffield Dental Institute).
Another boost to my team and mediated by the Anatomy Department (via D.R. Johnson) was the arrival of two experienced, young orthopaedic surgeons on consecutive fully-funded two-year research secondments from the Department of Orthopaedics (University of Sapporo, Japan).
Their presence initiated a project relating to Sharpey fibre signalling in response to exercise, on the one hand, and the micro-CT imaging of cancellous conservation by a bisphosphonate treatment for vertebral osteoporosis, on the other.
At the same time, and for a shorter period was the visit of a senior clinical scientist from Barcelona (M. Fernandez-Conde) wishing to apply our methods to the drug-related control of metastatic bone cancer to consolidate his publication on the subject.
Throughout this time I was requested to be External Examiner to PhD incumbents in Helsinki, London and Bristol, including one student formerly from NASA with a particularly topical thesis about the detrimental effects of space travel and zero gravity on the skeleton.
For a decade the charity Action Medical Research and its partners supported my interrelated series of project grant applications on skeletal fragility (despite/or because of the novelty having been described somewhere as a "a locally invented fantasy").
These investigations were clinically underpinned by Consultant Rheumatologist L.D. Hordon who as a junior doctor had performed histomorphometric observations for an MD in my laboratory, together with multicentre observations relating to renal osteodystrophy. Her senior location at Dewsbury District Hospital NHS Trust enabled a generous supply of ethically-approved femoral specimens from the orthopaedic surgeons.
Our partnership with Action Medical Research culminated in the presentation of our work at Buckingham Palace in the presence of HRH Duke of Edinburgh. There also followed the International Bone and Mineral Society (Washington) award of the Millenium Prize for Best Paper published in the leading journal BONE and personally received at the Joint Meeting of the IBMS and ECTS in Madrid in 2001.
With the completion of my 6 yr MRC extension I was appointed Lecturer within the School of Biomedical Sciences, where in addition to my research responsibilities and postgraduate supervision I began undergraduate teaching, including a final year module on bone diseases.
There also developed an interdisciplinary association with R. Wilcox (Institute of Medical and Biological Engineering, Leeds) leading to a joint major five-year award on the EPSRC Challenging Engineering Programme relating to the spine; this included a PhD student bursary and an opportunity for my former undergraduate student (P.E. Garner) to combine the complementary skills from both institutions into developing innovative computer-assisted tissue mapping technology for osteocyte populations and also for trabecular disconnection "hotspots" of weakness - procedures previously performed manually.
2009 - present:
My current appointment as Visiting Lecturer provides me with an essential writing platform, supported by like-minded members of my former laboratory team and with several academic papers in progress and a future book prospect (about a golgi-directed portal to bone biology).
Ongoing is an association with the Leeds Institute of Musculoskeletal Medicine and the development of a novel histological explanation for osteoarthritic bone marrow lesions, which may provide significant insight into an unrecognised aspect of normal lytic bone behaviour and recovery.
Presently, after the recent visit of senior maxillofacial surgeon Martin Chin from California, our fundamental research on trabecular generation/ regeneration and the previously unsuspected role of Sharpey’s fibres is finding a clinical application in innovative oral surgical restitution benefitting those most severely handicapped. We have since published a joint book chapter on the topic and he has named the outcome of our collaboration "Embryomimetic Surgery."
- Former Programme Manager
- Former Director Bone Structural Biology Laboratory
- Former PhD Supervisor
THE BONE MINERAL BIOSPHERE.
A Substructural Basis for Skeletal Fragility.
Histologically bone is more complex than often supposed: its mechanotransduction properties remain unclear and its hallmark hardness is sensitive to manipulation and prone to ultrastructural transformation. (It may be no coincidence that the term apatite means “the deceiver”).
The explanation for age-related skeletal fragility centres on negative turnover and a low mass measurement; less accessible for analysis are structural “quality” factors that are independent of the mass.
[Hordon, L., Raisi, M., Aaron, J.E., Paxton, S.K., Beneton, M., Kanis, J.A.: Trabecular architecture in women and men of similar bone mass, with and without vertebral fracture: I. Two-dimensional histology. Bone 27:271-276, 2000].
My laboratory began when there were few such in the world able to routinely section undecalcified bone (other than by sawing and milling) and the substructural properties it targets are recounted in more than 120 original articles, invited book chapters, reviews and symposium proceedings.
Primarily investigated are the microarchitectural and macromolecular changes to the demands imposed by age, physical activity, reproduction and metabolic bone disease, and with special attention to the mineralization process within the context of other cells and tissues that calcify with phosphate………… a biological perspective producing results that are often contrary to accepted doctrine.
Early publications provide a histomorphometric face to multidisciplinary investigations; others relate to unusual phenomena (e.g. with veterinarian A.D. Care, Leeds, and a PTH-related placental protein pump for calcium that directly effects foetal trabecular remodelling); many are clinical (e.g. seasonally-related osteomalacia in femoral fracture), while a few are serendipitous (e.g. with archaeologist J. Rogers, Bristol, confirming Paget’s disease in bone from a C16th burial ground).
[e.g. Aaron, J.E., Makins, N.B., I.W., Abbas, S.K., Pickard, D.W., Care, A.D.: The parathyroid glands in the skeletal development of the ovine foetus. Bone & Min 7: 13-22, 1989; Aaron, J.E., Gallagher, J.C., Nordin, B.E.C.: Seasonal variation of histological osteomalacia in femoral neck fractures. Lancet 2, 7872:84-85, 1974; Aaron, J.E., Rogers, J., Kanis, J.A.: Paleohistology of Paget’s disease in two medieval skeletons. Am.J.Phys.Anth. 89: 325-331, 1992].
In particular are novel aspects of bone biology in a theme that commenced independently during my doctorate. Enlightened by acquisition of a state-of-the-art Zeiss Photomicroscope it was to benefit subsequently from milestone advances in technology and cell biology, together with the advice of wise mentors, and the collective skills of technicians, undergraduate and postgraduate students, clinicians, global scientists and a biomedical engineer, each one of which never ceased to amaze.
[e.g. Aaron, J.E. Carter, D.H.: Rapid preparation of fresh frozen undecalcified bone for histological and histochemical analysis. J. Histochem. Cytochem. 35:361-369, 1987; Aaron, J.E., Johnson, D.R., Kanis, J.A., Oakley, B.A.. O’Higgins, P., Paxton, S.K.: An automated method for the analysis of trabecular bone structure. Comput. Med. Res. 25:1-16, 1992].
1. Fragility and the Disconnection Factor.
The resilience of the most vulnerable skeletal sites (wrist, spine, hip) depends on the cancellous bone microarchitecture. We established at the outset that bone loss with age differs significantly between the sexes: reduced formation causes trabecular thinning in men (and in steroid-induced osteoporosis in both sexes); in contrast, increased resorption causes trabecular loss in women (and in hypogonadal osteoporosis in both sexes) - the latter seriously disrupting network integrity.
[e.g. Aaron, J.E., Makins, N.B., Sagreiya, K.: The microanatomy of bone loss in normal aging men and women. Clin. Orthop. Rel. Res. 215:260-271, 1987; Aaron, J.E., Francis, R.M., Makins, N.B.: Contrasting microanatomy of trabecular bone loss in idiopathic and corticosteroid-induced osteoporosis. Clin. Orthop. Rel. Res. 243: 294-305, 1989].
*Implication: There are processes for thickening attenuated trabeculae (e.g. fluoride), BUT a mechanism for replacing their number is less clear, resulting in disconnected cancellous segments and a weakened framework.
Our search for potential avenues for trabecular restitution have included i) pathology (e.g. in Paget’s disease preliminary trabecular thickening is followed by intra-trabecular osteoclastic tunnelling regenerating reticulation); ii) embryogenesis by emulating de novo trabecular generation via its natural intramembranous scaffold of periosteal/endosteal fibres.
[e.g. Aaron, J.E., De Vernejoul, M-C., Kanis, J.A.: The effect of sodium fluoride on trabecular architecture in osteoporosis. Bone 12:307-10,1991. Aaron, J.E., De Vernejoul, M-C., Kanis, J.A.: Bone hypertrophy and trabecular generation in Paget’s disease and in fluoride-treated osteoporosis. Bone & Min. 17: 399-413, 1992; Carter, D.H., Sloan, P., Aaron, J.E.: Trabecular generation de novo. Anat. Embryol. 186:229-240, 1992; Aaron, J.E., Skerry, T.M.: Intramembranous trabecular generation in normal bone. Bone Min 25, 211-30, 1994].
The impact on skeletal fragility of the trabecular disconnection phenomenon for skeletal fragility was demonstrated by reference to the mechanically-contrasting, ubiquitous conditions of osteoporosis (i.e. low impact, fracture-prone) and osteoarthritis (i.e. high impact, non-fracture) as comparative, stress-related tools. Of central relevance to interpretation was some novel biomechanical cell behaviour with compelling evolutionary consequences for the calcification event, as follows.
2. Stress conductance within a Golgi-directed bone mineral biosphere.
While the golgi apparatus performs minimally in the initiation and direction of the calcification process in typically soft tissues, in hard tissues like bone it is maximally differentiated for established metabolic and biomechanical purposes. (With longevity golgi-directed discrimination between soft and hard tissues declines, paradoxically permitting soft tissues to harden and hard ones to soften, with potential pathological consequences).
Protozoan adaptation to stress. The apparent origin of the golgi apparatus in skeletal mineralization is best illustrated in the large, contractile protozoan Spirostomum ambiguum. Its juxtanuclear organelle “switches on” to copiously fabricate micron-sized objects calcified with phosphate (similar to those in bone) and to polarise their alignment relative to its naturally stressful habit of burrowing in silt. On adopting a less stressful aquatic swimming mode it “switches off” and randomly unloads much of its particulate cargo to the medium, any remainder retained as a metabolic mineral reserve.
*Conclusion: A protozoan model of the juxtanuclear golgi apparatus as a key intraosseous receptor of extraneous forces and its counteraction of mineral particle fabrication is contrary to the established view of vertebrate calcification as extracellular epitactic crystal growth passively subject to ritual laws of physics and chemistry.
[Fallon, V., Garner, P.E., Aaron, J.E.: Mineral fabrication and golgi apparatus activity in Spirostomum ambiguum: a primordial paradigm of the stressed bone cell? J Biomed Sci Eng 10:466-483, 2017; Aaron, J.E.: Osteocyte types in the developing mouse calvarium. Calc. Tiss. Res. 12:259-279, 1973].
Vertebrate adaptation to stress. Our evidence suggests that the quiescent and typically compact juxtanuclear body, when energised by extraneous stress and expanded for bone mineral fabrication basically recapitulates the intracellular protozoan stress-initiated event. There follows, the extracellular, polarised dissemination of the calcified particles with reference to 4 integrated networks, configured according to regional biomechanical demand.
I. Mineral particulate INITIATION: the osteocyte syncytial network. A golgi-directed cycle of calcium phosphate/carbonate loading and unloading (each about 15 min duration) occurs in “young” osteocytes located at the advancing calcification front of developing bone (using von Kossa, GBHA or tetracycline stain).
[Aaron, J.E., Pautard, F.G.E.: Dynamic studies of bone mineralization in vivo by incident light interference contrast microscopy. In: Calcified Tissues (Czitober,J., Eschberger, J.eds) Facta-Publication, Vienna:197-201, 1973.]
In cultured osteocytes where the dynamic process responds to external manipulation this prominent golgi-initiated process is confirmed (using a specific FGP-tagged construct) and is systematically stopped by the golgi inhibitor brefeldin A and restarted by the stimulant forscolin.
In situ, the regionally diverse capacity of the osteocyte syncytium to engage with the extracellular matrix is captured by our ”in house” system combining confocal laser microscopy with image analysis software and novel binary masks enabling the definition, separation and mapping of cell features for quantification (as osteocyte number and size, process volume and density, interconnection and polarity).
* Results: A less cellular, disconnected syncytium characterises the low-stress condition osteoporosis, in contrast to high-stress osteoarthritis where cytoplasmic process volume was high and disconnection low, features in keeping with a difference in golgi body capacity and mechanotransduction distinction between the two conditions.
[Fallon, V., Carter, D.H., Aaron J.E.: Mineral fabrication and golgi apparatus activity in the mouse calvarium. J Biomed Sci Eng 7,769-779, 2014; Garner, P.E, Wilcox, R., Aaron, J.E.: Quantification of cell networks: computer-assisted method for 3D mapping of osteocyte populations in the ageing human femur. IBMS BoneKEy 10: Article 333: S26-7, 2013].
II. Mineral particulate ASSEMBLY: the inorganic microskeletal network. Following their extrusion from the osteocytes golgi-fabricated calcified microspheres accumulate in the extracellular matrix as discrete objects (of bacterial dimension) or interlinked into chains and convoluted bridged-assemblies, to create an independent microskeletal network of regional diversity, encircling and contiguous with the collagen type I matrix fibrous bundles.
The complex inorganic particles are organically enshrouded (lipid, bone sialoprotein, osteocalcin and variably contain osteopontin, tenascin and fibronectin) and remain amorphous or of differentially-controlled crystallinity. They constitute mosaic-like domains of indigenous histochemical diversity (e.g. acid phosphatase and carbonic anhydrase activity, and including RNA positivity) and autoclastic potential (an inherent hydrolytic capacity for rapid self-destruction without the later refinement and precision of osteoclastic mediation, i.e. a “crumple zone” equipped to absorb excess energy).
They can be harvested from the organic matrix by various milling and digestion processes for future analysis and they are preserved in the fossil remains comprising Khourigba phosphorite (used as a fertiliser).
[e.g. Aaron, J.E., Oliver, B., Clarke, N., Carter D.H.: Calcified microspheres as biological entities and their isolation from bone. Histochem J 31: 455-470, 1999; Aaron, J.E.: Autoclasis – a mechanism of bone resorption and an alternative explanation for osteoporosis. Calcif. Tissue Res. 22:247-254, 1976].
Morphologically organelle-like, the microspherical objects have less dense centres surrounded by electron dense beaded filamentous (5nm) clusters that pair into ladder-like configurations. They may derive from precursor nanospheres (40-250nm), are inherently capable of budding and possess variable traces of carbonate and of Si, Mg, Al, Fe etc. as inorganic modulators of their physicochemical behaviour.
[e.g. Aaron, J.E., Pautard, F.G.E.: Ultrastructural features of phosphate in developing bone cells. Israel J. Med. Sci.8: 625-629, 1972; Carter, D.H, Hatton, P.V., Aaron, J.E.: The ultrastructure of slam-frozen bone mineral. Histochem.J. 29:783-93, 1997].
The calcified microspheres tend to remain uncoupled in functionally unloaded, primarily protective regions, e.g. fish scales (acellular bone). In contrast, in axially-loaded tubular dentine they become deformed and their interlinkage compressed as polarised ultrastructural struts and stays.
[e.g. Carter, D.H., Sloan, P., Aaron, J.E.: The cryomocrotomy of the rat dental tissues: a technique for histological and immunohistochemical analysis. Histochem.J. 26,103-109, 1994; Carter, D.H., Scully, A.J., Heaton, D.A., Young, M.P.J., Aaron, J.E.: Effect of deproteination on bone morphology: implications for biomaterials and aging. Bone 31, 389-95, 2002].
*Results: Measurements indicate that relative to stress factors, the microspheres are too small in low-stress osteoporosis (0.5 microns) constituting a fine microskeletal assembly, and too large in high-stress osteoarthritis (2 microns) creating a coarse one. As well as influencing fragility, such textural differences may modulate fluid flow and mechanotransduction (in a manner familiar to gardeners of differing water-retentive clay and sandy soil).
[Linton, K.M.,Hordon, L.D., Shore, R.C., Aaron, J.E.: Bone mineral “quality”: differing characteristics of calcified microsphere populations at the osteoporotic and osteoarthritic femoral articulation front. J. Biomed. Sci. Eng. 7:739-755, 2014].
III. Mineral particulate AXIAL POLARIZATION: the periosteal Sharpey’s fibre network. Traditionally these birefringent fibres are confined to providing superficial anchorage for the periosteal membrane. Our evidence suggests that they may also conduct incipient force across their uncalcified, intraosseous expanse of uncalcified networks, the ramifications of which traverse the collagen type I laminated matrix, some reaching marrow spaces to couple with the endosteal rim, and thereby enclosing a discrete circle of influence and control (including remodelling).
They directly integrate intramembranous bony tissue with muscle, ligament and tendon insertions, on occasion “hijacking” the foundation platform provided by an earlier, immature endochondral model.
Their average insertion angle, prominence and permeation tends to diminish with age and their finest, most distal, fan-like branches are only visualised by specific fluorescent antibody markers. They reach maximum prevalence within the defined boundary of a proximal femoral domain and also within the exceptionally powerful porcine mandible.
[e.g. Al-Qtaitat, A., Shore, R.C., Aaron, J.E.: Structural changes in the ageing periosteum using collagen III immune-staining and chromium labelling as indicators. J. Musculoskelet. Neuronal Interact.10:112-123, 2010].
Derived from the periosteum the fibres are apparently fundamental to embryonic trabecular development and to skeletal repair as a scaffold for osteogenic cell assembly.
Augmented in youth and by physical activity, the uncalcified fibres, 15-25 microns thick, are comprised of collagen type III/ VI macromolecules beaded with the biological organiser tenascin and encircled with elastin. With age and oestrogen decline they calcify and shorten in advance of matrix loss.
[e.g. Carter, D.H., Sloan, P., Aaron, J.E.; Immunolocalization of collagen types I and III, tenascin and fibronectin in intramembranous bone. J Histochem Cytochem39:599-606, 1991; Luther, F., Saino, H.,Carter, D.H., Aaron, J.E.: Evidence for an extensive collagen Type III/VI proximal domain in the rat femurI. Diminution with ovariectomy. Bone 32:652-659, 2003; Saino, H., Luther, F., Carter, D.H., Natali,A.J., Turner, D.L., Shahtaheri, S.M., Aaron, J.E.: Evidence for an extensive collagen Type III proximal domain in the rat femur. Expansion with exercise. Bone 32:660-668, 2003].
Their slender fibrous interspersion among the microskeletal assemblies may facilitate signal trafficking preparatory to targeted endosteal remodelling (a turnover process from which they are themselves generally protected until age-related random calcification hardens them).
*Results: In low-stress osteoporosis, the periosteal Sharpey fibre system is fine and fragmented, befitting poor intraosseous perception of muscular input; in high-stress osteoarthritis the system is coarse and continuous, conducive with high extraneous force perception.
[e.g. Aaron, J.E.: Periosteal Sharpey’s fibres: a novel bone matrix regulatory system? Frontiers in Endocrin 3:98- , 2012].
IV. Mineral particulate MULTIAXIAL SUPPORT: the trabecular network. The marshalled mineral assemblages within the bony tissue influence, in particular, the microarchitectural properties of the cancellous network by virtue of their variable nature, remodelling propensity and stability (i.e. particle slip or crystalline microfracture).
[Aaron, J.E.; Bone turnover and microdamage. Advances in Osteop. Fract. Management 2:102-110, 2003].
Cancellous integrity is a major determinant of strength at the most multiaxial, fracture-prone skeletal locations and a susceptibility to trabecular disconnections (particularly cross struts) reduces the strength in excess of the quantity of tissue lost (i.e. doubling the distance between cross struts weakens fourfold).
Disconnections are rare in youth (except in pregnancy and lactation where their occurrence is apparently reversible).
[e.g. Shahtaheri, S.M., Aaron, J.E., Johnson, D.R., Purdie, D.W.: Changes in the trabecular architecture of women during pregnancy. Brit. J. Obs, Gynaecol. 106:432-438, 1999].
The incidence and distribution pattern of trabecular disconnections with age determines their combined impact and predictability.
To identify and map disconnections under the microscope our simple “in house” (international prize-winning) manual method solved the major problem of separating real trabecular termini (ReTm) from planar histological sectioning artefacts by displaying the 2-dimensional cancellous image within its 3-dimensional context, thereby pinpointing their distribution.
[e.g. Aaron, J.E., Shore, P.A., Shore, R.C., Kanis, J.A.: Trabecular architecture in women and men of similar bone mass: II. Three dimensional histology. Bone 27:277-82, 2000].
Our most recent “in house” combination of image analysis software and microcomputed tomography scanning produces comprehensive computer-generated constructs of trabecular disconnection, mapping their incidence and fracture potential.
[Garner, P.E., Wilcox, R., Aaron, J.E.: A direct computer-assisted method for the spatial 3D mapping of trabecular termini in the spine. IBMS BoneKey 10; Article 333:S14-15, 2013].
*Results: In the low-stress osteopenic female hip and spine disconnections multiply into predictable “hotspots” at sites of tension (ultimately releasing “floating” cancellous segments of minor structural value); their distribution differs in men where they are fewer and closer to the vertebral endplates. In high-stress osteoarthritis disconnections are random and capricious, sometimes causing macroscopic subchondral bone marrow lesions (BML, about 10mm diameter) of hydrolytic destruction (autoclasis) and repair. Treatment with bisphosphonates apparently protects from hypogonadal disconnection.
[Aaron, J.E. Shore, P.A., Itoda, M., Morrison, R.J.M.;Hartopp, A., Hensor, E.M.A., Hordon L.D.l: Mapping trabecular disconnection “hotspots” in aged human spine and hip. Bone 78:71-80, 2015; Hordon, L.D., Itoda, M., Shore, P.A.,Kanis, J.A., Rodan, G.A., Aaron, J.E.: Preservation of thoracic spine microarchitecture by alendronate: comparison of histology and microCT. Bone 38: 444-449, 2006].
The particulate bone mineral biosphere: a primordial legacy.
Protozoan beginnings? The evolutionary significance for backbones of an otherwise apparently undistinguished protozoan (described above) was suggested by Pautard (1959, 1961). Now combined with our golgi body-extrapolation to bone cell behaviour there follows the possibility that chronic bone fragility may derive from an underperforming golgi program imprinted on the versatile apparatus in antiquity to protect delicate protozoa in the silt when their pond dries out.
Prokaryote beginnings? Bacteria may predate the protozoan golgi body in bone mineral fabrication, as suggested by the prokaryote-directed assembly of similar microspheres and precursor nanospheres (40-250nm) calcified with phosphate in a silicon-rich intracellular intermediary in the lifecycle of a bacterial model (Corynebacterium matruchotii).
Pre-prokaryote beginnings? Precedent to prokaryotes may be the emergence of a silicified primordial particle through an ancient geological portal whereby the omnipresence of silicon in bacterium, protozoan and osteocyte alike derive from its singular property of facilitating calcium phosphorylation via carbonate in biological systems.
[Linton, K. Tapping, C.R., Adams, D.G.,Carter, D.H., Shore, R.C., Aaron, J.E.: A silicon cell cycle in a bacterial model of calcium phosphate mineralogenesis. Micron 44:419-432, 2013; Aaron, J.E. Cellular ubiquity of calcified microspheres: a matter of degree, ancient history and the golgi body J Biomed Sci 5:3, 2016 and also in Top 10 Contributions in Biomed Sci, 2nd Ed. Ch. 3 AvidSciencei.com, 2018].
*Postulation: On the “road to backbones” the golgi-fabricated inorganic bone biosphere may be a Gram positive, “petrified microbiome” composed of populations of vestigial prokaryotes or pre-prokaryotes………?
…….and so ad infinitum…...
If aspects of the proposed periosteal-encompassed and Sharpey’s fibre permeated microcosm seem unlikely, recent clinical applications reported by others include:
- improved bio-implant integration by Sharpey’s fibres in the most complex oral and maxillofacial surgery named “Embryomimetics” (M. Chin, California);
- treatment for over-loaded periosteal Sharpey’s fibres in Schlatter’s Syndrome where microfissures accumulate in the over-stimulated knees of teenage footballers during the signal-rich growth spurt (T. Maseide, Norway);
- excessive torsion in Sharpey fibre anchorage of degenerate, collapsing discs causing vertebral epiphyseal rim erosion found in archeological remains (M. Dobson, London).
[Chin, M., Aaron, J.E.: Sharpey fibre biologic model for bone formation. In: The Sinus Bone Graft. 3rd Ed.(O.T. Jensen, ed) Quintessence Publishing Berlin, Chicago, London, 2019].
- In place of the widespread view of a collagenous matrix stiffened with uniform sheets of microcrystallites is proposed an inorganic bone biosphere of considerable complexity.
- Consisting of populations of golgi-fabricated microspheral objects (1 micron) calcified with phosphate it is the putative evolutionary legacy of a contractile protozoan.
- Initially confined to the “switched on” osteocyte syncytium, their monitored extrusion into a compressed environment causes microspherical compaction and deformity within the boundaries of mosaic-like matrix domains (30 microns).
- Exposure to multiaxial pressures directs their assembly into a mineral microskeleton permeated by periosteal Sharpey fibre arrays in a partnership with the osteocyte golgi body that defines the bedrock resilience constituting each individual trabecula of the cancellous network.
- Abnormalities in either the recipient microspheres (with the behaviour of functional organelles) or transmitting periosteal envelope (and Sharpey fibre/ endosteal continuum) may predispose to trabecular disconnection, disproportionate weakness and the basis of stress-related disability.
GOLGI-DIRECTED BIOSPHERE: The particulate, microskeletal assembly of calcium phosphate by bone cells is predicated by a primordial and compliant golgi apparatus programmed for complex mineral fabrication in a contractile, intermittently-stressed protozoan.
PERIOSTEAL STRESS CONDUCTANCE AND NETWORK FAILURE: Chronic diminution and retraction of a) regionally integrated networks of intraosseous periosteal Sharpey’s fibres reduces tensile signals to b) cohorts of interlinked osteocyte golgi bodies and c) their matrix microskeletal assemblies, thereby d) consigning host trabeculae to perceived disuse resulting in e) cancellous obsolescence, disconnection, “floating segments" and structural weakness.
(Another song to sing…….?)<h4>Research projects</h4> <p>Any research projects I'm currently working on will be listed below. Our list of all <a href="https://biologicalsciences.leeds.ac.uk/dir/research-projects">research projects</a> allows you to view and search the full list of projects in the faculty.</p>
- BSc Applied Biology, Bradford
- PhD Bone Biology, Leeds
Previously I taught general histology and also head and neck gross anatomy to large classes of human biologists, medical students, biomedical scientists, physiotherapists, midwives and radiographers.
I managed final year undergraduate research projects (library and laboratory) which fulfilled the principle of "teaching in a research environment." This furnished my laboratory with a valuable annual intake of 6 or more highly motivated undergraduate finalists undertaking projects of mainstream relevance to my programme, all made possible by the experienced technical guidance of P.A. Shore. These undergraduates sometimes merited publication as coauthors. In addition were occasional students on Summer Vacation Scholarships.
Complementary to my research theme was my final year module on "Bone in Health & Disease" which attracted a large group of students to sessions including:1.Normal age-related bone histology.2. Osteoporosis.3. Non-invasive methods (special reference to osteoporosis). 4. Bone by invasion. 5. Bone hormones and reproduction. 6. Bone turnover and Paget's disease. 7. Bone coping with stress, and Bone conquering the Cosmos. 8. Fractures and the self-repairing skeleton. 9. Osteoarthritis and tartar toothpaste.10. Rickets, osteomalacia and the "Englische Krankheit."
[Doctors dream (for various reasons), Of finding some rare and unusual lesions, Hoping to shed some original light on The problem - and line up a subject to write on. (Michael M. Stewart M.D.)]