In vertebrates, PTH receptor 1 (PTH1R) plays a pivotal role in control of bone development and homeostasis; however, how it is regulated is poorly defined. Here we report that Kindlin-2 binds to and modulates PTH1R to regulate bone mass and PTH actions. Deleting Kindlin-2 expression using the 10-kb mouse Dmp1-Cre severely impairs the anabolic effects of intermittent PTH on bone in adult mice with or without ovariectomy. Of particular interest, Kindlin-2 and Pth1r double heterozygous mice (Dmp1- Cre; Kindlin-2 f/+ ; Pth1r f/+ ), but not either singly heterozygous mice (Dmp1- Cre; Kindlin-2 f/+ or Dmp1-Cre; Pth1r f/+ ), display severe osteopenia and fail to increase bone mass in response to administration of intermittent PTH. Mechanistically, Kindlin-2 interacts with the C-terminal cytoplasmic region of PTH1R. When overexpressed, this region efficiently inhibits the endogenous PTH/PTH1R signaling in osteoblasts, which is reversed by introduction of a point mutation that abolishes the Kindlin-2 interaction. Furthermore, Kindlin-2 loss inhibits PTH-induced CREB phosphorylation and cAMP production in vitro and in bone. PTH upregulates, while estrogen deficiency downregulates, expression of Kindlin-2 in vitro and in bone. Collectively, we demonstrate that interplay between Kindlin-2 and PTH1R regulates bone mass by modulating PTH1R and provide a potential therapeutic target for metabolic bone diseases

Orientador: Bruno Watanabe Minto / Resumo: Os traumas ósseos desencadeiam resposta inflamatória aguda e consequentemente alteram a concentração sérica das proteínas de fase aguda (PFAs), podendo essas serem um parâmetro para avaliação da evolução do processo inflamatório relacionado a ortopedia. Objetivou-se avaliar a efetividade da mensuração de PFAs como um biomarcador laboratorial para diagnóstico e acompanhamento da inflamação relacionada a regeneração óssea. Foram utilizados 22 coelhos, machos jovens sendo realizado ostectomia parcial do osso do rádio direito. Para acompanhamento da evolução do processo inflamatório foram realizados hemograma, mensuração de PFAs (Albumina, Ceruloplasmina, Haptoglobina, Proteína C Reativa e Transferrina) e acompanhamento radiológico. Foi observado a melhor correlação da haptoglobina e da transferrina junto ao processo inflamatório e achados radiológicos frente as demais PFAs mensuradas. A haptoglobina apresentou pico máximo 24 horas dos pós operatório e a transferrina após 36 horas, entretanto essa última PFA já mostrou indícios de alteração (diminuiu) já nas primeiras 6 horas do pós-cirúrgico, antecipadamente a resposta leucocitária. Conclui-se que o conjunto haptoglobina, transferrina e leucograma apresentaram resultados promissores ao diagnóstico e prognóstico de processos inflamatórios relacionados a ortopedia. / Doutor

Indiana University-Purdue University Indianapolis (IUPUI) / Current interventions used to reduce skeletal fragility are insufficient at enhancing bone across multiple hierarchical levels. Bisphosphonates, such as Zoledronate (ZOL), treat a variety of bone disorders by increasing bone mass and bone mineral density to decrease fracture risk. Despite the mass-based improvements, bisphosphonate use has been shown to compromise bone quality. Alternatively, Raloxifene (RAL) has recently been demonstrated to improve tissue quality and overall mechanical properties by binding to collagen and increasing tissue hydration in a cell-independent manner. We hypothesized that a combination of RAL and ZOL would improve mechanical and material properties of bone more than either monotherapy alone by enhancing both quantity and quality of bone. In this study, wildtype (WT) and heterozygous (OIM+/-) male mice from the Osteogenesis Imperfecta (OI) murine model were treated with either RAL, ZOL, or RAL and ZOL from 8 weeks to 16 weeks of age. Combination treatment resulted in higher trabecular architecture, cortical mechanical properties, and cortical fracture toughness in diseased mouse bone. Two fracture toughness properties, direct measures of the tissue’s ability to resist the initiation and propagation of a crack, were significantly improved with combination treatment in OIM+/- compared to control. There was no significant effect on fracture toughness with either monotherapy alone in either genotype. Following the mass-based effects of ZOL, bone volume fraction was significantly higher with combination treatment in both genotypes. Similar results were seen in trabecular number. Combination treatment resulted in higher ultimate stress in both genotypes, with RAL additionally increasing ultimate stress in OIM+/-. RAL and combination treatment in OIM+/- also produced a higher resilience compared to the control. Given no significant changes in cortical geometry, these mechanical alterations were likely driven by the quality-based effects of RAL. In conclusion, this study demonstrates the beneficial effects of using combination therapy to increase bone mass while simultaneously improving tissue quality, especially to enhance the mechanical integrity of diseased bone. Combination therapies could be a future mechanism to improve bone health and combat skeletal fragility on multiple hierarchical levels.

Sexual dimorphism has been noted to exist in many genera of birds, but it is not until recently that papers have appeared which deal with the actual extent of sexual dimorphism and its possible adaptive significance. The papers of Rand (1952), Sibley (1957), Amadon (1959), and Selander (1966) hypothesize about the possible significance of sexual dimorphism in birds, and the papers of Kilham (1965), Selander (1965), Storer (1966), Ligon(1968), Ingolfsson (1969), and Verner and Willson (1969) examine the relationship between hypotheses on the significance of sexual dimorphism and actual field conditions. None of these papers deals with differences in bone or muscle ratios which may exist between the sexes. A paper by Engels (1938a) on variation in bone length and limb proportion in the coot does examine differences in bone length and limb proportions due to sex, but only in a very cursory manner. It appears that only the most obvious and well known sexually dimorphic birds, i.e. woodpeckers, birds-of-paradise, accipitrines, have been studied. In this paper my purpose is to ascertain osteological and myological differences between the sexes of a bird which does not have a great deal of apparent sexual dimorphism - Sturnella neglecta neglecta Audubon, A.O.U. 501.1.

M.Sc., Faculty of Science, University of the Witwatersrand, 2011 / The aim of this investigation was to explore the relationship between the unidentified and identified fauna from the Still Bay period at Blombos Cave between ca. 77 and 72 ka. The size, breakage patterns and surface modifications of unidentified long bone fragments from the M1 and upper M2 phases were analysed. The results of the analyses were then compared to a sample of faunal remains identified by Klein (Henshilwood et al. 2001b) and Thompson (2008) from the Still Bay layers at Blombos Cave. The length of each fragment was measured to ascertain the degree of fragmentation of the assemblage. Long bone fragments generally become slightly shorter with increasing depth. This may be because smaller fauna are relatively more prevalent in the deeper layers. Cortical thickness of the bone fragments was measured and grouped into small, medium and large categories. These categories were correlated to Brain‟s (1974a) bovid size classes to investigate whether the unidentified faunal remains mimic the identified bone sample in terms of animal size. While small-sized fauna dominate the identified archaeofaunal assemblages at Blombos Cave, the cortical thickness of unidentified long bone fragments suggest that medium-sized fauna was more common. The breakage pattern of each fragment was assessed, indicating that the majority of specimens exhibited spiral fractures. Burning is more common in the unidentified faunal sample than in the identified sample and may have resulted in the relatively low frequencies of cut-marked and percussion-marked fragments. Polished bone fragments may also be a consequence of burning, abrasion or compaction, though its prevalence in the upper M2 with formal bone tools suggests that it was the result of human activities. Higher bone fragment densities in the upper layers at Blombos Cave suggests that changes in human occupation and faunal density patterns during the Still Bay at Blombos Cave may relate to environmental conditions.

Osteoporosis is a disease that may be pre-determined from the condition of bone health during youth. In South Africa, the situation is quite unique in that the population of black people has a reduced fracture rate compared to white people. As lifestyle and dietary patterns change with urbanisation and there is a shift towards westernised diets and sedentary behaviour in youth, fractures in elderly South African blacks may become more prevalent. With these rapid lifestyle changes, it will become increasingly important to prioritise osteoporosis and its related conditions as a major public health concern in South Africa. Very few of the factors influencing osteoporosis have been well studied in children of different ethnic groups. Physical activity in childhood, especially in the prepubertal years, confers residual benefits to the adult skeleton. In this thesis, the associations between ethnicity, history of participation in physical activity and skeletal health were explored in a sample of pre-/early pubertal children from South Africa who participated in four different studies. Furthermore, a novel aspect of the thesis was the use of peripheral quantitative computed tomography (pQCT) to investigate the mechanistic role that physical activity plays on bone health in this unique population. First the use of an existing physical activity questionnaire for the assessment of bone loading had to be validated in a sample of black and white boys and girls (n=38). A bone loading algorithm was used to calculate a peak bone strain score (PBSS) from the physical activity questionnaire. Therefore a bone specific physical activity questionnaire (B3Q) was used in subsequent studies. The PBSS was shown to be reliable and reproducible with significant (p<0.001) intraclass correlation coefficients. There were significant correlations between PBSS and moderate (r=0.38; p=0.02), vigorous (r=0.36; p=0.03) and combined moderate to vigorous intensity activity counts (r=0.38; p=0.02) as measured by accelerometry. The ability of the PBSS algorithm to classify children into high or low weight bearing groups was in moderate agreement with accelerometer derived combined moderate and vigorous activity counts (κ=0.42; p=0.008). PBSS was significantly correlated to body size adjusted bone mineral content at all sites scanned by DXA (r=0.43-0.57; p<0.05). Positive correlations were observed between PBSS and area, density and strength at the radius and tibia (r=0.40-0.64; p<0.05). At the radial metaphysis, significant correlations between moderate activity (r=0.46; p=0.005) and combined moderate and vigorous activity counts (r=0.42; p=0.01) were seen for bone strength. No associations were seen between accelerometer measured physical activity and bone outcomes at the tibial diaphysis. Multiple regression analysis showed that the PBSS was a better predictor of bone mass and structure than was accelerometry. The next study sought to determine whether children who were classified as being high bone loaders for the past two years would present with greater bone mass and strength regardless of their ethnicity. Sixty six children [black boys, 10.4(1.4) yrs, n=15; black girls, 10.1(1.2) yrs, n=27; white boys, 10.1(1.1) yrs, n=7; white girls, 9.6(1.3) yrs, n=17] reported on all their physical activities over the past two years in the interviewer administered bone specific physical activity questionnaire (B3Q). Children were classified as being either high or low bone loaders based on the cohort’s median peak bone strain score estimated from the B3Q. In the low bone loading group, black children had greater femoral neck bone mineral content (BMC) (2.9 (0.08)g) than white children (2.4 (0.11)g; p=0.05). There were no ethnic differences in the high bone loaders for femoral neck BMC. At the cortical sites, the black low bone loaders had a greater radius area (97.3 (1.3) vs 88.8 (2.6) mm2 ; p=0.05) and a greater tibia total area (475.5 (8.7) vs. 397.3 (14.0) mm2 ; p=0.001) and strength (1633.7 (60.1) vs. 1271.8 (98.6) mm3 ; p=0.04) compared to the white low bone loaders. These measures were not different between the black low and high bone loaders or between the black and white high bone loaders. Ethnic differences in bone area and strength apparent between children classified as having a lower bone loading physical activity history appear to have been attenuated when children partaking in high bone loading physical activities were compared. Greater levels of mechanical loading seemed to have no apparent benefits in black children. Cross-sectional studies in black and white pre-pubertal children have observed significant ethnic differences in structural bone outcomes as measured by pQCT but there are a limited number of intervention studies that have been conducted in black children. The cortical bone of black and white children may respond differently to mechanical forces, yet no physical activity interventions and their effects on bone structure in black children have been done. The aim of the third study was to determine whether a weight-bearing physical activity intervention improves measures of bone mass, structure and strength in pre-pubertal black children. Children (9.7 ± 1.1 years) were randomised into an exercise (EX; n=12) and control (CON; n=11) group. The EX children performed a 20-week weightbearing exercise program performed twice a week for 45 minutes per session, while CON children continued their regular activities. Changes in tibial trabecular volumetric bone density, area and strength were greater in the EX than the CON group (all p<0.01). At the cortical site of the tibia, the change in bone density was greater in the EX group than the CON group (all p<0.05). The greater change in tibial periosteal circumference in the EX groups also resulted in a greater change in cortical thickness of the tibia compared to the CON group (p<0.05). The final study assessed whether rates of bone accrual differed over one year between high and low bone loaders and also between black and white South African children. Forty seven children (18 boys, 29 girls) were followed up after one year. High bone loaders tended to have greater baseline BMC at all sites measured by DXA but the difference was only significant at the femoral neck (p=0.03). At the follow up visit, femoral neck BMC remained significantly higher in the high compared to the low bone loaders (p=0.003). Bone strength index (BSI) at the follow up visit was significantly greater in the high bone loaders compared to the low bone loaders (p=0.05). Although there was a trend for the high bone loaders to have greater indices of density and area at the 65% tibia compared to the low bone loaders, this was not significantly different at baseline or at follow up. High bone loaders had greater relative changes in whole body BMC (p=0.002), tibial cortical area (p=0.03), cortical density (p=0.04) and cortical thickness (p=0.03) compared to low bone loaders. There were no significant differences in DXA bone outcomes between black and white children at baseline and follow up. At baseline, total density at the 4% radius was greater in black than in white children (p<0.001) but total density at the follow up visit was not significantly different between black and white children (p=0.06). Trabecular density was greater in the black than in the white children at baseline (p=0.01) as well as at follow up (p=0.04). BSI at baseline was greater in the black than in the white children (p=0.05) but this significance disappeared at follow up. Similar to the 4% radius, cortical density at baseline was significantly greater in the black compared to the white children at the 65% radius (p=0.01) and at the 65% tibia (p=0.04). In conclusion, the PBSS algorithm from the B 3Q can be used to reliably and accurately collect data on previous participation in weight bearing exercise and is able to classify children as being either high or low bone loaders. It appears that in order for White children to reach the same bone mass/health levels as Black children, they may need to participate in higher levels of weight-bearing physical activity. Ethnic differences in bone area and strength apparent between children classified as having a lower bone loading physical activity history appear to have been attenuated when children partaking in high bone loading physical activities were compared. The associations may indicate that a strong environmental influence (i.e. high participation in physical activity) may offer similar or even superior benefits to bone over genetic (ethnic) influences. The use of pQCT appears to be sufficiently sensitive in detecting bone structural changes in response to mechanical loading interventions. As such, pQCT measures were able to determine the efficacy of a weight bearing physical activity intervention on trabecular and cortical sites in black children, and, similar to what has previously been observed in white and Asian children, our knowledge on the attainment of bone in response to an exercise intervention in black children is deepened. Moreover, the bone accrual that occurs in a population of black and white children from a low-middle income country may also differ between ethnicities and may reflect an environmental influence that modifies existing paradigms on physical activity and bone health in children. The promotion of weightbearing physical activity should occur in all youth, to oppose the possible lifestyle induced risks for developing osteoporosis in adulthood.

Original published work submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy, August 2019 / Age-at-death estimates in skeletal remains are hampered by observer bias and error, as well as individual and population variation. This study aimed at improving accuracy and reliability of age estimates obtained from applying methods involving the assessment of histomorphometric variables of bone and bone mineral density (BMD). The assessment of osteon population density (OPD) and size (length, surface area and volume) of Haversian systems were investigated in three populations by means of stereology. Bone slides prepared from South African black (n = 99), South African white (n = 94) and Danish white (n = 30) individuals were analysed using MicroBrightField’s StereoInvestigator software. ANCOVA results revealed a statistically significant difference (p < 0.001) between the three groups in terms of OPD. No statistically significant difference was seen in the size of secondary osteons between the groups. Linear regression analysis was used to construct population-specific formulae for age-atdeath estimation in South African white and black individuals. The Danish sample was used as a comparative group for white South African standards established. Age mimicry appeared to play a role in the over-estimation of age in the Danish individuals, after which the problem was corrected by combining the two samples in order to achieve normal age distribution within the larger sample. Secondly, DXA scans of the proximal femur were done for a subgroup of South African black (n = 64) and white (n = 59) individuals for estimation of age-at-death from bone mineral density. Results displayed a significant difference between white and black groups for total and neck BMD. White males and females differed in total and neck BMD, although black males and females differed only in terms of neck BMD. Age could be significantly correlated with BMD in the white population, but not in the black population. Regression analysis was also done for the complete sample (white and black individuals pooled), as ancestry is unknown in some cases. A significant correlation was seen for age versus neck BMD in the total sample and in sex-specific groups. The outcome of this study suggested that the three population samples are somewhat dissimilar in bone microstructure, with differences related to OPD and BMD present between the groups. Based on this outcome, it should be emphasized that age estimation standards should be adapted to accommodate combined groups and create to more generally applicable standards. Further research involving various disciplines is needed to better understand the underlying reason(s) for these differences between these populations. / PH2020

Indiana University-Purdue University Indianapolis (IUPUI) / Endosseous implants have been accepted as a viable dental and medical adjunct and are now used for multiple dental applications. The majority are placed in patients of relatively advanced age, and, as such, the increased use of implants has raised questions in the areas of bone healing and metabolism associated with their placement. This study evaluated the mechanical and histological aspects of the bone/metal interface of endosseous titanium implants in compact and trabecular bone. Two implants were placed: one in the distal metaphysis (M) and one 2.0 cm proximal in the diaphysis (D). Right side limbs were subjected to a sham surgery and served as controls. The rabbits were sacrificed at six, 12, and 24 weeks healing time. Multiple fluorochrome labels were given to mark sites of bone formation. At sacrifice, all implants were tested for interface torque strength. Microradiography and fluorescent light microscopy were used to determine percent volume of bone and marrow space, bone/implant interface characteristics, percent labeled bone surface area, and percent labeled bone volume. D implants required about 20 percent more torque to mechanically disrupt the bone/implant interface than M implants. Values were M (combined groups) 33.4 N-cm ±15.5 N-cm, and D (combined groups) 41.5 N-cm ±16.0 N-cm (Mean ±SD, n = 8, p<.07). The percent of bone in direct contact with the implant surface appeared to increase only slightly with time. Direct contact occurred on 11.2%, 9.5% ±8.5% and 13.9% ±6.6% of the M implant surface in six, 12, and 24 week specimens, respectively. Direct contact occured on 11.7%, 10.2% ±2.4% and 19.5% ±0.35% of the D implant surface in six, 12, and 24 week specimens, respectively. Total bone volume in implanted D specimens was less [Exp.= 91.1% ± 3.1%, Cont. = 95.5% ± 0.73% (Mean ±SD)] and marrow space volume was greater [Exp. = 8.9% ±3.02%, Cont. = 4.6% ±0.73% (Mean ±SD)] than in controls (p<.02). The percent labeled bone volume was greater in the implanted specimens than in their controls (p<.001). This difference decreased over time. Implanted D specimens also showed significantly more (p<.001) labeled bone surface area than controls. These findings suggest that when implants are placed in elderly subjects, normally inactive bone becomes very active. Also, it seems that bone quality, not quantity, determines interface strength.

Thesis (Ph.D. (African Languages)) -- University of Limpopo, 2019 / Muhumbulo muhulwane wa ngudo, wo vha wa u sedzulusa na u sengulusa mbonalo ya mushumo wa vhutunguli nga ṅanga dza sialala ḽa mvelele ya Tshivenḓa. Ṱhoḓisiso yo vha yo sedzesaho kha tshenzhemo na vhupfiwa ha ṅanga dza sialala nga ha kuvhonele kwavho kwa mushumo wa vhutunguli kha mushumo wavho wa ḓuvha ḽiṅwe na ḽiṅwe. Tsenguluso yo vha ya u fhaṱusa lushaka nga ha ndeme ya vhutunguli kha vhutshilo ha ḓuvha ḽiṅwe na ḽiṅwe na u khakhulula kuhumbulele kwo shandeaho nga ha vhutunguli ha sialala ḽa Vhavenḓa sa vhu no fhura vhathu tshelede ngeno mishumo yaho i sa tendisei. Ngudo yo sumbedza vhuvha ha mushumo wa vhutunguli ha sialala u bva tsikoni u swika ṋamusi na thuso ine ya vhu ṋetshedza miṱani na kha shango, u tsivhudza lushaka nga u vhamba maano a u vhulunga nḓivho na uri i nga pfukiselwa hani kha vhaswa. Ho shumiswa madzhenele a khwalithethivi kha u kuvhanganya mafhungo. Mafhungo o kuvhanganywa nga nḓila ya inthaviyu vhathu vho livhana zwifhaṱuwo na nga luṱingo khathihi na u ṱalela nyito. Mafhungo o kuvhanganyiwaho o khoudiwa nga maitele a hone, ha bveledzwa thero. Thero dzo tumbulwaho dzo kona u livha kha mawanwa na themendelo. Tsedzuluso yo vhonala yo vula lushaka maṱo kha u dzhiela vhutunguli ha sialala nṱha.

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