Dale Rick Sumner

Disrupted intestinal epithelial barrier function has been proposed to be integral to rheumatoid arthritis (RA) progression and pathogenesis. To further define the molecular pathways in synovial inflammation and the response of the intestinal tissues, we have used a rat model of mono-joint inflammatory arthritis, induced by intra-articular injection of Complete Freund’s adjuvant (CFA). The predominant inflammatory response of a single injection of the adjuvant into the knee joint resulted in rapid and reproducible formation of a fibrotic myeloid-infiltrated synovial pannus. Our aim was to determine how intestinal tissues, including the proximal and distal ileum and distal colon, responded to inflammatory changes in the synovium in a temporally coordinated manner by comparing their transcriptomic landscapes using RNASeq analyses. We confirmed the timeline of joint inflammation by knee joint swelling measurement, increased synovial fluid levels of bikunin (a component of both the acute phase protein pre-alpha-inhibitor and inter-alpha-inhibitor) and demonstrated a self-correcting response of trabecular and cortical bone to the CFA challenge. Intestine-specific responses were monitored by 16S microbiome amplicon sequencing, histopathology for mucus layer integrity, and immune cell immunohistochemistry. We present data that shows the intestinal tissue displays an allostatic response to the acute joint inflammation and was region specific. The ileum primarily responded with increased mucus secretion and silencing of T-cell specific pathways, whereas the colon showed a transient upregulation of macrophages, with a broader suppression of immune related and metabolic pathway related transcripts. Interestingly, many neuropathways were activated early but then suppressed later in both the ileum and colon. There were only insignificant changes in the fecal microbiome composition in ileum or colon post-CFA administration. In summary, our data show for the first time a suppression of intestinal inflammatory and immune responses following the induction of joint inflammation and only minimal and transient changes in the microbiome. The results help clarify the molecular responses of intestinal tissues to inflammatory stresses that accompany the pathogenesis of inflammatory joint diseases.

The International Society of Bone Morphometry (ISBM) is dedicated to advancing research, education, and clinical practice for osteoporosis and other bone disorders by developing and improving tools for the quantitative imaging and analysis of bone. Its initial core mission was to promote the proper use of morphometric techniques in bone research and to educate and train clinicians and basic scientists in bone morphometry. This article chronicles the evolution of the ISBM and the history and development of bone morphometric techniques for the past 50-years, starting with workshops on bone morphometry in 1973, to the formal incorporation of the ISBM in 1996, to today. We also provide a framework and vision for the coming decades. This effort was led by ISBM presidents Dr Erica L. Scheller (2022-2024) and Dr Thomas J. Wronski (2009-2012) in collaboration with all other living ISBM presidents. Though the underlying techniques and questions have changed over time, the need for standardization of established tools and discovery of novel approaches for bone morphometry remains a constant. The ISBM fulfills this need by providing a forum for the exchange of ideas, with a philosophy that encourages the open discussion of pitfalls and challenges among clinicians, scientists, and industry partners. This facilitates the rapid development and adaptation of tools to meet emerging demands within the field of bone health at a high level.

Preterm birth affects about 10% of all live births with many resultant health challenges, including metabolic bone disease of prematurity (MBDP), which is characterized by elevated alkaline phosphatase, suppressed phosphate, and deficient skeletal development. Because of the lack of an animal model, very little is known about bone structure, strength, and quality after preterm birth. This study investigated the utility of a pig model to replicate clinical features of preterm birth, including MBDP, and sought to determine if early postnatal administration of IGF-1 was an effective treatment. Preterm pigs, born by caesarean section at 90% gestation, were reared in intensive care facilities (respiratory, thermoregulatory, and nutritional support) and compared with sow-reared term pigs born vaginally. Preterm pigs were systemically treated with vehicle or IGF-1 (recombinant human IGF-1/BP-3, 2.25 mg/kg/d). Tissues were collected at postnatal days 1, 5, and 19 (the normal weaning period in pigs). Most bone-related outcomes were affected by preterm birth throughout the study period, whereas IGF-1 supplementation had almost no effect. By day 19, alkaline phosphatase was elevated, phosphate and calcium were reduced, and the bone resorption marker C-terminal crosslinks of type I collagen was elevated in preterm pigs compared to term pigs. Preterm pigs also had decrements in femoral cortical cross-sectional properties, consistent with reduced whole-bone strength. Thus, the preterm pig model replicates many features of preterm bone development in infants, including features of MBDP, and allows for direct interrogation of skeletal tissues, enhancing the field’s ability to examine underlying mechanisms.

In 2021, the American Association for Anatomy (AAA) Board of Directors appointed a Task Force on Structural Racism to understand how the laws, rules, and practices in which the Association formed, developed and continues to exist affect membership and participation. This commentary is the first public report from the Task Force. We focus on African Americans with some comments on Jews and women, noting that all marginalized groups deserve study. Through much of its 130 year history, some members were an essential part of perpetuating racist ideas, the Association largely ignored racism and had some practices that prevented participation. The Task Force concluded that individual and structural racism within the AAA, combined with the broader social context in which the Association developed, contributed to the current underrepresentation of African Americans who constitute 4.1% of the membership even though 13.4% of the U.S. population is Black. Intentional efforts within the AAA to reckon with racism and other forms of bias have only begun in the last 10–20 years. These actions have led to more diverse leadership within the Association, and it is hoped that these changes will positively affect the recruitment and retention of marginalized people to science in general and anatomy in particular. The Task Force recommends that the AAA Board issue a statement of responsibility to acknowledge its history. Furthermore, the Task Force advocates that the Board commit to (a) sustaining ongoing projects to improve diversity, equity, and inclusion and (b) dedicating additional resources to facilitate novel initiatives.

Many lifestyle factors affect bone. Sleep deprivation increases risk for fractures and alcohol consumption can lead to alterations in the skeleton. How combined exposure to these two risk factors affects bone is unclear. Thus, we sought to determine the effects of circadian rhythm disruption and chronic alcohol intake on bone structure and mechanical properties in mice. A total of 120 male C57BL/6J mice were used in two cohorts of 60 mice each because of limited availability of light‐tight housing cabinets. One cohort was born in winter and the other in summer. Mice were randomly assigned to circadian disruption (weekly shifting of the light/dark cycle) and control (no shifting) groups beginning at 8 to 12 weeks of age for 12 weeks at which time mice were administered an alcohol‐containing or control diet for an additional 10 weeks. Bone structure and mechanical properties of the femur were assessed by micro‐computed tomography and three‐point bending, respectively. The initial data analysis revealed a likely cohort effect. Thus, we used a three‐way analysis of variance to assess the effects of circadian rhythm disruption, alcohol intake, and cohort. Circadian rhythm disruption alone had minimal effects on bone structure and mechanical properties. Alcohol intake reduced body mass and had minimal effects on cortical bone regardless of circadian disruption. Alcohol intake resulted in higher trabecular bone volume, but these beneficial effects were blunted when circadian rhythm was disrupted. Cohort significantly affected body size, many cortical bone structure outcomes, some trabecular bone structure outcomes, and tissue‐level material properties. Thus, cohort had the predominant effect on bone structure and mechanical properties in this study, with chronic alcohol intake and environmental circadian disruption having less consistent effects. The data indicate that season of birth may affect skeletal phenotypes and that studies requiring multiple cohorts should determine if a cohort effect exists. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Canonical Wnt signaling plays an important role in skeletal development, homeostasis, and both endochondral and intramembranous repair. While studies have demonstrated that the inhibition of Wnt signaling impairs intramembranous bone regeneration, how its activation affects intramembranous bone regeneration has been underexplored. Therefore, we sought to determine the effects of activation of canonical Wnt signaling on intramembranous bone regeneration by using the well‐established marrow ablation model. We hypothesized that mice with a mutation in the Wnt ligand coreceptor gene Lrp5 would have accelerated intramembranous bone regeneration. Male and female wild‐type and Lrp5‐mutant mice underwent unilateral femoral bone marrow ablation surgery in the right femur at 4 weeks of age. Both the left intact and right operated femurs were assessed at Days 3, 5, 7, 10, and 14. The intact femur of Lrp5 mutant mice of both sexes had higher bone mass than wild‐type littermates, although to a greater degree in males than females. Overall, the regenerated bone volume in Lrp5 mutant male mice was 1.8‐fold higher than that of littermate controls, whereas no changes were observed between female Lrp5 mutant and littermate control mice. In addition, the rate of intramembranous bone regeneration (from Day 3 to Day 7) was higher in Lrp5 mutant male mice compared to their same‐sex littermate controls with no difference in the females. Thus, activation of canonical Wnt signaling increases bone mass in intact bones of both sexes, but accelerates intramembranous bone regeneration following an injury challenge only in male mice.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestinal tract and is associated with decreased bone mineral density. IBD patients are at higher risk of osteopenia, osteoporosis and fracture compared to non-IBD patients. The impact of IBD on the performance of orthopedic implants has not been well studied. We hypothesized that a history of IBD at the time of primary total hip arthroplasty (THA) would increase the risk of subsequent failure as assessed by revision surgery. A retrospective implant survival analysis was completed using the Swedish Hip Arthroplasty Registry and the Sweden National Patient Register. A total of 150,073 patients undergoing THA for osteoarthritis within an 18-year period were included in the study. THA patients with (n = 2,604) and without (n = 147,469) a history of IBD at the time of THA were compared with primary revision as the main endpoint and adjusted using sex, age category and comorbidity (Elixhauser scores) as covariates. We found that patients with a history of IBD had a relatively higher risk of revision surgery for septic causes while the non-IBD patients had a relatively higher risk of revision for aseptic causes (p = 0.004). Our findings suggest there may be an association between gut health and THA performance.

The circadian clock system regulates multiple metabolic processes, including bone metabolism. Previous studies have demonstrated that both central and peripheral circadian signaling regulate skeletal growth and homeostasis. Disruption in central circadian rhythms has been associated with a decline in bone mineral density and the global and osteoblast-specific disruption of clock genes in bone tissue leads to lower bone mass. Gut physiology is highly sensitive to circadian disruption. Since the gut is also known to affect bone remodeling, we sought to test the hypothesis that circadian signaling disruption in colon epithelial cells affects bone. We therefore assessed structural, functional, and cellular properties of bone in 8 week old Ts4-Cre and Ts4-Cre;Bmal1 ^fl/fl (cBmalKO) mice, where the clock gene Bmal1 is deleted in colon epithelial cells. Axial and appendicular trabecular bone volume was significantly lower in cBmalKO compared to Ts4-Cre 8-week old mice in a sex-dependent fashion, with male but not female mice showing the phenotype. Similarly, the whole bone mechanical properties were deteriorated in cBmalKO male mice. The tissue level mechanisms involved suppressed bone formation with normal resorption, as evidenced by serum markers and dynamic histomorphometry. Our studies demonstrate that colon epithelial cell-specific deletion of Bmal1 leads to trabecular and cortical bone loss in male mice.