Mechanical Adaptation Of Bone Research Articles

A microbiome-dependent gut-bone axis determines skeletal benefits from mechanical loading

A recent study published in Cell Metabolism entitled “Gut microbial alterations in arginine metabolism determine bone mechanical adaptation” demonstrated that administration of L-arginine enhanced bone mechanical adaptation by activating a nitric oxide-calcium feedback loop in osteocytes. The findings revealed that mechanical regulation of bone adaptation is associated with gut microbiota. The underlying cause of heterogeneity of bone mechanoresponsiveness was the significant difference in the composition of the gut microbiota, in which the family Lachnospiraceae contributed to the inter-individual high variability in bone mechanical adaptation. Additionally, administration of Lachnospiraceae exhibited increased expression levels of L-citrulline and L-arginine and enhanced bone mechanoresponsiveness in recipients. Collectively, this study provides mechanistic insights into inter-individual variability of the gut microbial, which is related to the heterogeneity of bone mechanical adaptation and provides a novel preventive and therapeutic strategy to anti-osteoporotic for maximizing bone mechanoresponsiveness via the microbiota-metabolite axis.

Skeletal adaptation to mechanical cues during homeostasis and repair: the niche, cells, and molecular signaling.

Bones constantly change and adapt to physical stress throughout a person's life. Mechanical signals are important regulators of bone remodeling and repair by activating skeletal stem and progenitor cells (SSPCs) to proliferate and differentiate into bone-forming osteoblasts using molecular signaling mechanisms not yet fully understood. SSPCs reside in a dynamic specialized microenvironment called the niche, where external signals integrate to influence cell maintenance, behavior and fate determination. The nature of the niche in bone, including its cellular and extracellular makeup and regulatory molecular signals, is not completely understood. The mechanisms by which the niche, with all of its components and complexity, is modulated by mechanical signals during homeostasis and repair are virtually unknown. This review summarizes the current view of the cells and signals involved in mechanical adaptation of bone during homeostasis and repair, with an emphasis on identifying novel targets for the prevention and treatment of age-related bone loss and hard-to-heal fractures.

Mapping the Response of Human Osteocytes in Native Matrix to Mechanical Loading Using RNA Sequencing.

Osteocytes sense mechanical loads and transduce mechanical signals into a chemical response. They are the most abundant bone cells deeply embedded in mineralized bone matrix, which affects their regulatory activity in the mechanical adaptation of bone. The specific location in the calcified bone matrix hinders studies on osteocytes in the in vivo setting. Recently, we developed a three-dimensional mechanical loading model of human osteocytes in their native matrix, allowing to study osteocyte mechanoresponsive target gene expression in vitro. Here we aimed to identify differentially expressed genes by mapping the response of human primary osteocytes in their native matrix to mechanical loading using RNA sequencing. Human fibular bone was retrieved from 10 donors (age: 32-82 years, 5 female, 5 male). Cortical bone explants (8.0 × 3.0 × 1.5 mm; length × width × height) were either not loaded or mechanically loaded by 2000 or 8000 μɛ for 5 minutes, followed by 0, 6, or 24 hours post-culture without loading. High-quality RNA was isolated, and differential gene expression analysis performed by R2 platform. Real-time PCR was used to confirm differentially expressed genes. Twenty-eight genes were differentially expressed between unloaded and loaded (2000 or 8000 μɛ) bone at 6 hours post-culture, and 19 genes at 24 hours post-culture. Eleven of these genes were related to bone metabolism, ie, EGR1, FAF1, H3F3B, PAN2, RNF213, SAMD4A, and TBC1D24 at 6 hours post-culture, and EGFEM1P, HOXD4, SNORD91B, and SNX9 at 24 hours post-culture. Mechanical loading significantly decreased RNF213 gene expression, which was confirmed by real-time PCR. In conclusion, mechanically loaded osteocytes differentially expressed 47 genes, of which 11 genes were related to bone metabolism. RNF213 might play a role in mechanical adaptation of bone by regulating angiogenesis, which is a prerequisite for successful bone formation. The functional aspects of the differentially expressed genes in bone mechanical adaptation requires future investigation. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

A Three-Dimensional Mechanical Loading Model of Human Osteocytes in Their Native Matrix

Osteocytes are mechanosensory cells which are embedded in calcified collagenous matrix. The specific native matrix of osteocytes affects their regulatory activity, i.e., transmission of signaling molecules to osteoclasts and/or osteoblasts, in the mechanical adaptation of bone. Unfortunately, no existing in vitro model of cortical bone is currently available to study the mechanosensory function of human osteocytes in their native matrix. Therefore, we aimed to develop an in vitro three-dimensional mechanical loading model of human osteocytes in their native matrix. Human cortical bone explants containing osteocytes in their three-dimensional native matrix were cultured and mechanically loaded by three-point bending using a custom-made loading apparatus generating sinusoidal displacement. Osteocyte viability and sclerostin expression were measured 1–2 days before 5 min loading and 1 day after loading. Bone microdamage was visualized and quantified by micro-CT analysis and histology using BaSO4 staining. A linear relationship was found between loading magnitude (2302–13,811 µɛ) and force (1.6–4.9 N) exerted on the bone explants. At 24 h post-loading, osteocyte viability was not affected by 1600 µɛ loading. Sclerostin expression and bone microdamage were unaffected by loading up to 8000 µɛ. In conclusion, we developed an in vitro 3D mechanical loading model to study mechanoresponsiveness of viable osteocytes residing in their native matrix. This model is suitable to study the effect of changed bone matrix composition in metabolic bone disease on osteocyte mechanoresponsiveness.

A retrospective survey of an implant, designed to resist bone loss

Introduction: A significant percent of dental implants tends to lose bone support during the years. Gravity implants were designed to improve the mechanical bone adaptation in an attempt to overcome the problem. The present manuscript is a retrospective observation of 1 year of 25 single-loaded Gravity implants. Materials and Methods: This was a retrospective study of files of patients who completed their treatment and were loaded for 1 year. The measurement of changes in the bone level was done according to the X-ray documentations that were found in the files of patients treated in the clinic of Kibutz Bror Chail. The schedule of dental implants' follow-up in this clinic includes parallel periapical X-ray films at the stage of implant installation, the stage of loading, and at the end of a year of loading. A Student's t-test was used to compare the bone level at the stage of loading and after 1 year of loading. Results: Twenty-five cases of one single-loaded implant per patient were included in the study. It was shown that most of the bone loss that was documented at the end of the healing phase was reconstructed (72%) during 1 year of loading. Conclusions: According to this retrospective study, it can be concluded that implant design that enables bone loading by compressive stress may result in the reconstruction of the initial loss.

Resistive exercise with or without super‐imposed whole‐body vibration acutely induces bone resorption

BackgroundExercise is one of the well‐known constituents to improve bone mass and to retain bone strength. Only few studies have reached the effects of resistive exercise on sclerostin levels, a protein that is thought to play a key role in orchestrating bone's mechanical adaptation. Sclerostin is produced and released by osteocytes and acts as an inhibitor of bone formation through inhibition of the Wnt/β‐catenin‐signaling pathway. The objective of this study was to evaluate acute and long‐term effects of exercise on bone biochemical marker expression. More specifically, we aimed to understand differences in the responses to resistance exercise with or without whole‐body vibration.MethodsA six week training intervention was performed including 26 healthy males (26 years, SD=4) in in a randomized parallel design. Performing either resistive exercise (RE, n=13) or resistive vibration exercise (RVE, n=13) training, with weekly increasing vibration frequencies 20–40 Hz. Serum samples were collected both at the initial and final exercise session. Changes in carboxy‐terminal cross‐linked telopeptide of type I collagen (sCTX‐I), as a marker of bone resorption, and of procollagen type I amino terminal propeptide (P1NP) as a specific marker of bone formation as well as serum sclerostin concentrations were measured via ELISA (sCTX‐I and sclerostin) or RIA (P1NP) measurements.ResultsSerum markers of sCTX‐I decreased by 15% within the first minutes following either training intervention, both regarding the initial and final training session. Subsequently, levels of sCTX‐I returned back to pre‐bout baseline after RE (time effect: P<0.001), and they depicted an overshoot by 18% after 75 min. Serum levels of P1NP depicted an acute increase by 15% to exercise (P<0.001). P1NP levels were non‐substantially increased in RE at the end of the 6 week intervention (P<0.001), but decreased by 10% in RVE, as compared to baseline (P< 0.001). Pre‐bout levels of sclerostin were marginally lowered at the end of the 6 week training phase. After the exercise bouts, sclerostin levels increased within the first minutes both RE and RVE (time effect: P<0.001). Notably, sclerostin responses to the initial exercise bouts differed significantly between RE and RVE P=0.029.ConclusionThe present findings suggest that in young healthy adults both conditions RE and RVE elicited an acute exercise‐induced bone resorption without any acute change in bone formation. Results are compatible with the idea that this response was mediated by sclerostin.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Functional morphology in the pages of the AJPA

Functional morphology in the pages of the <i>AJPA</i>

A novel implant designed to improve mechanical bone adaptation

Research shows an exaggerated bone loss adjacent to installed implants during the healing period. This phenomenon may continue later along the years in a slower rate. Sometimes, there is even an acceleration of the phenomenon during the years. The presented implant was designed to restore short-term bone loss caused during the healing phase and to slow and even prevent long-term bone loss. The result is achieved by emitting at the bone, mainly, compressive stress vectors that are essential for improved mechanical bone adaptation, including organization of bone into load-bearing type and modeling of the bone by enlarging its volume. This case report shows how a nonfunctional bone architecture turns into a load-bearing type and how initial bone loss may be restored after implant loading.

Simulation of Bone Mechanical Adaptation in a 3D Model of the Proximal Femur Using the Stanford Strain Energy Density Approach

The mathematical theories of bone mechanical adaptation are based on a nonlinear ordinary differential equation which governs the evolution of bone density with respect to the applied loads. If the density distribution achieved within a certain bone model resembles the expected distribution observed in the real bone, then the mathematical theory is usually thought to be suited for such simulations. As test problem, it was extensively used the coronal section of the proximal femur. This section inspired the very creation of the mathematical models following Wolff’s observations regarding trabecular architecture. However, the lack of quantitative data when using the bi dimensional femur model prevents the quantitative validation of the adaptation mathematical models. Using computed tomography is now possible to reconstruct the three dimensional geometry of bones and also to estimate the apparent density based on correlations with the Hounsfield units. This method was already used to quantitatively validate the simulation of bone remodeling into different bones and proved to be efficient. The paper presents the apparent density distributions achieved into the 3D model of the proximal femur by coupling the finite element method with the Stanford bone adaptation equation. The densities obtained in this manner are compared by those determined from the tomographic data of the same bone. The purpose relies on establishing whether the three dimensional end proximity of the femur bone can be used for quantitative validation of remodeling simulations.

Osteocyte density in the peri‐implant bone of implants retrieved after different time periods (4 weeks to 27 years)

Bone tissue is characterized by a constant turnover in response to mechanical stimuli, and osteocytes play an essential role in bone mechanical adaptation. However, little to no information has been published regarding osteocyte density as a function of implantation time in vivo. The aim of this retrospective histological study was to evaluate the osteocyte density of the peri-implant bone in implants retrieved because of different reasons in a time period from 4 weeks to 27 years. A total of 18 samples were included in the present study. Specimens were divided into 3 groups depending on the loading history of the implants: loading between 4 weeks and 7 months (group 1); loading between 1 and 5 years (group 2); loading between 14 and 27 years (group 3). All the samples were histologically evaluated and osteocyte density was obtained using the ratio of the number of osteocytes to the bone-area (mm(2) ). The osteocyte density values significantly increased in the Group 2 (1-5 years) compared with Group 1 (4 weeks-7 months), and significantly decreased in the Group 3 (14-27 years) compared to Group 2. No significant differences were detected between Group 1 and Group 3. The decrease in osteocyte density observed in samples that were in vivo for long periods of time under loading is possibly because of the fact that once the bone structure is well aligned and biomechanically competent, a lower number of osteocytes are necessary to keep the tissue homeostasis under loading.

Quantifying load-induced solute transport and solute-matrix interaction within the osteocyte lacunar-canalicular system

Osteocytes, the most abundant cells in bone, are essential in maintaining tissue homeostasis and orchestrating bone's mechanical adaptation. Osteocytes depend upon load-induced convection within the lacunar-canalicular system (LCS) to maintain viability and to sense their mechanical environment. Using the fluorescence recovery after photobleaching (FRAP) imaging approach, we previously quantified the convection of a small tracer (sodium fluorescein, 376 Da) in the murine tibial LCS under intermittent cyclic loading. In the present study, we first expanded the investigation of solute transport using a larger tracer (parvalbumin, 12.3 kDa), which is comparable in size to some signaling proteins secreted by osteocytes. Murine tibiae were subjected to sequential FRAP tests under rest-inserted cyclic loading while the loading magnitude (0, 2.8, or 4.8 N) and frequency (0.5, 1, or 2 Hz) were varied. The characteristic transport rate k and the transport enhancement relative to diffusion (k/k0) were measured under each loading condition, from which the peak solute velocity in the LCS was derived using our LCS transport model. Both the transport enhancement and solute velocity increased with loading magnitude and decreased with loading frequency. Furthermore, the solute-matrix interaction, quantified in terms of the reflection coefficient through the osteocytic pericellular matrix (PCM), was measured and theoretically modeled. The reflection coefficient of parvalbumin (σ = 0.084) was derived from the differential fluid and solute velocities within loaded bone. Using a newly developed PCM sieving model, the PCM's fiber configurations accounting for the measured interactions were obtained for the first time. The present study provided not only new data on the micro-fluidic environment experienced by osteocytes in situ but also a powerful quantitative tool for future study of the PCM, the critical interface that controls both outside-in and inside-out signaling in osteocytes during normal bone adaptation and in pathological conditions.

Vitamin D supplementation during pregnancy and pregnancy outcomes

Vitamin D supplementation during pregnancy and pregnancy outcomes

NO signaling in mechanical adaptation of bone

NO signaling in mechanical adaptation of bone

Role of osteocyte apoptosis in peculiar ossicles of the hearing sense organ: preliminary observations on hearing loss and osteoporosis

Starting point of the present study is the osteocyte role in bone remodelling that allows bone adaptation to mechanical load [1-3]. Bone remodelling has been investigated in relation to the occurrence of apoptosis [4] to understand if and how the process of programmed cell death interferes with bone turnover. In 1998, in a study on human middle ear, Marotti et al. [5] demonstrated that: 1) over 40% of osteocytes are dead within the 2nd year of age (but the authors were not able to demonstrate if osteocyte death occurred by degeneration or apoptosis); 2) bone remodelling occurs only occasionally. Recently [6], we showed that: 1) osteocytes of human auditory ossicles die by apoptosis; 2) also osteocytes located inside scleral ossicles of lower vertebrate eye (reptiles and birds) phylogenetically so far from human auditory ossicles are widely affected by apoptosis (about 60%); 3) in scleral ossicles bone turnover never occur. It is to be noted that both auditory ossicles of human ear and scleral ossicles of vertebrate eye are peculiar bony segments continuously submitted to stereotyped stresses and strains, with specialized functions: the first are involved in sound wave transmission and the latter protect the eyeball against deformation during the movement and have a role in visual accomodation, providing attachment for the ciliary muscles. In both cases, bone remodelling might severely impair, by resorption, the mechanical resistance of these extremely small specialized bony segments. Thus, we suggested that in auditory and scleral ossicles, submitted to stereotyped loading for all life, bone mechanical adaptation is not needed and osteocyte programmed death could represent the mechanism to avoid bone remodelling and to make stable, when necessary, bone structure and mechanical resistance. More recently, to confirm this hypothesis, clinical data were collected from a cohort of patients aged 55-85 years affected by hearing loss. The main target of the present study is to exclude any correlation between hearing loss and osteoporosis. During osteoporosis, unbalanced bone turnover causes the bone depletion in skeletal segments; such condition, in the peculiar ossicles of human middle ear, should imply hearing impairment. Our preliminary observations indicate, instead, that osteoporotic patients do not show higher percentage of hearing loss with respect to non osteoporotic ones. This evidence is ascribable to osteocyte apoptosis of auditory ossicles that avoid bone remodelling, thus assuring the integrity of such bony segments also in osteoporotic conditions.

Occlusal load transmission to bone via the periodontal attachment apparatus

A mathematical model for occlusal load transmission to the bone via the periodontium is suggested in this manuscript. According to this model the unique mechanical qualities of the periodontal ligament space enable it to process impact forces into pure normal stress vectors that compress the nearby bone. Normal stress vectors are a very effective mean for bone bending. Distortion of the bone is a prerequisite for initiation mechanical bone adaptation. Bending of the bone while there are shear stress vectors may hamper bone adaptation. In contrary to natural tooth attachment, osseointegration attachment that contributes dental implants, enables bending of the bone while risking bone attached to the implant by shear stress. This model may explain the radiating arrangement of bone’s trabeculae around natural root, the usually lack of this phenomenon around dental implants and the bone absorption around dental implants.

Mechanical Loading Stimulates BMP7, But Not BMP2, Production by Osteocytes

Bone mechanical adaptation is a cellular process that allows bones to adapt their mass and structure to mechanical loading. This process is governed by the osteocytes, which in response to mechanical loading produce signaling molecules that affect osteoblasts and osteoclasts. Bone morphogenic proteins (BMPs) are excellent candidates as signaling molecules, but it is unknown whether mechanically stimulated osteocytes affect bone adaptation through BMP production. Therefore, the aim of this study was to assess whether osteocytes produce BMPs in response to mechanical loading. In addition, since BMP7 has a vitamin D receptor (VDR) response element in the promoter region, we also investigated whether VDR is involved in the BMP7 response to mechanical loading. Human or VDR(-/-) mouse primary bone cells were submitted in vitro to 1h pulsating fluid flow (PFF) and postincubated without PFF (PI) for 1-24h, and gene and protein expression of BMP2 and BMP7 were quantified. In human bone cells, PFF did not change BMP2 gene expression, but it upregulated BMP7 gene expression by 4.4- to 5.6-fold at 1-3h PI and stimulated BMP7 protein expression by 2.4-fold at 6h PI. PFF did not stimulate BMP7 gene expression in VDR(-/-) mouse bone cells. These results show for the first time that mechanical loading upregulates BMP7, likely via the VDR, but not BMP2, gene and protein expression in osteocytes in vitro. Since BMP7 plays a major role in bone development and remodeling, these data might contribute to a better understanding of the mechanism leading to the mechanical adaptation of bone.

Early activation of the β-catenin pathway in osteocytes is mediated by nitric oxide, phosphatidyl inositol-3 kinase/Akt, and focal adhesion kinase

Bone mechanotransduction is vital for skeletal integrity. Osteocytes are thought to be the cellular structures that sense physical forces and transform these signals into a biological response. The Wnt/β-catenin signaling pathway has been identified as one of the signaling pathways that is activated in response to mechanical loading, but the molecular events that lead to an activation of this pathway in osteocytes are not well understood. We assessed whether nitric oxide, focal adhesion kinase, and/or the phosphatidyl inositol-3 kinase/Akt signaling pathway mediate loading-induced β-catenin pathway activation in MLO-Y4 osteocytes. We found that mechanical stimulation by pulsating fluid flow (PFF, 0.7±0.3Pa, 5Hz) for 30min induced β-catenin stabilization and activation of the Wnt/β-catenin signaling pathway. The PFF-induced stabilization of β-catenin and activation of the β-catenin signaling pathway was abolished by adding focal kinase inhibitor FAK inhibitor-14 (50μM), or phosphatidyl inositol-3 kinase inhibitor LY-294002 (50μM). Addition of nitric oxide synthase inhibitor l-NAME (1.0mM) also abolished PFF-induced stabilization of β-catenin. This suggests that mechanical loading activates the β-catenin signaling pathway by a mechanism involving nitric oxide, focal adhesion kinase, and the Akt signaling pathway. These data provide a framework for understanding the role of β-catenin in mechanical adaptation of bone.

Inhibition of bone resorption reduces osteoarthritis in mice with high bone turn over

Mechanical adaptation of bone is a cellular process that allows bone to adjust its mass and structure to its mechanical environment. Such remodeling occurs by recruitment and activation of osteoclasts and osteoblasts in relation to strain distribution over bone tissue. These mechanical changes are detected by osteocytes, which results in production of signalling molecules such as nitric oxide (NO). We have shown earlier that mechanically stimulated osteocytes inhibit osteoclast formation via soluble factors, thus affecting bone resorption. We hypothesize that mechanically stimulated osteocytes modulate osteoclast formation by changing expression of osteoclastogenesis-related genes. Therefore, we investigated whether mechanical stimulation affects osteoclastogenesis-related gene expression in osteocytes. MLO-Y4 osteocytes were seeded at 10 cells/cm on glass slides in α-MEM with 5% FBS and 5% FCS. Osteocytes were mechanically stimulated by 1 h pulsating fluid flow (PFF;0.7±0.3 Pa,5 Hz), and post-incubated for 1 h and 6 h without PFF. Controls were kept under static culture conditions. NO production was determined as parameter of bone cell responsiveness. After 1 h PFF and 1 h and 6 h postincubation, cells were lysed for total RNA isolation. Gene expression of MEPE, PHEX, sclerostin, RANKL, and OPG was studied using real time-PCR. Within 5 min PFF increased NO production by 2.0-fold. PFF upregulated MEPE gene expression by 23.0-fold after 1 h, but not at 1 h and 6 h post-incubation. PFF did not affect PHEX expression. Sclerostin expression was not detectable. PFF upregulated RANKL expression by 2.1 fold, and OPG expression by 2.7 fold. PFF decreased the RANKL/OPG ratio by 20% after 1 h, but not at 1 h and 6 h post-incubation. Our data suggest that mechanical loading induces changes in osteoclastogenesis-related gene expression in osteocytes, which likely contributes to the inhibition of osteoclastogenesis after mechanical loading of bone. Since mechanical loading upregulated gene expression of MEPE but not of PHEX, possibly resulting in the upregulation of OPG gene expression, we speculate that MEPE might be a key soluble factor produced after mechanical loading of osteocytes leading to the inhibition of osteoclastogenesis.

Pulsating fluid flow modulates gene expression of proteins involved in Wnt signaling pathways in osteocytes

Strain-derived flow of interstitial fluid activates signal transduction pathways in osteocytes that regulate bone mechanical adaptation. Wnts are involved in this process, but whether mechanical loading modulates Wnt signaling in osteocytes is unclear. We assessed whether mechanical stimulation by pulsating fluid flow (PFF) leads to functional Wnt production, and whether nitric oxide (NO) is important for activation of the canonical Wnt signaling pathway in MLO-Y4 osteocytes. MC3T3-E1 osteoblasts were studied as a positive control for the MLO-Y4 osteocyte response to mechanical loading. MLO-Y4 osteocytes and MC3T3-E1 osteoblasts were submitted to 1-h PFF (0.7 +/- 0.3 Pa, 5 Hz), and postincubated (PI) without PFF for 0.5-3 h. Gene expression of proteins related to the Wnt canonical and noncanonical pathways were studied using real-time polymerase chain reaction (PCR). In MLO-Y4 osteocytes, PFF upregulated gene expression of Wnt3a, c-jun, connexin 43, and CD44 at 1-3-h PI. In MC3T3-E1 osteoblasts, PFF downregulated gene expression of Wnt5a and c-jun at 0.5-3-h PI. In MLO-Y4 osteocytes, gene expression of PFF-induced Wnt target genes was suppressed by the Wnt antagonist sFRP4, suggesting that loading activates the Wnt canonical pathway through functional Wnt production. The NO inhibitor L-NAME suppressed the effect of PFF on gene expression of Wnt target genes, suggesting that NO might play a role in PFF-induced Wnt production. The response to PFF differed in MC3T3-E1 osteoblasts. Because Wnt signaling is important for bone mass regulation, osteocytes might orchestrate loading-induced bone remodeling through, among others, Wnts.

Role of osteocytes in the adaptation of bone to mechanical loading

The mechanical performance of our skeleton is secured by the constant adaptation of bone to its mechanical loading environment. Mechanical adaptation of bone is brought about by the coordinated actions of osteoclasts and osteoblasts, which are orchestrated by the most mechano-sensitive cells in bone, the osteocytes. Loading on bone generates a flow of interstitial fluid through the lacuno-canalicular network in which the osteocytes are positioned. This flow is sensed by the osteocytes, which respond by the release of signaling factors such as nitric oxide, prostaglandins and Wnts, which alter the recruitment and activity of osteoblasts and osteoclasts, thereby affecting bone mass. Thus, any factor that alters the response of osteocytes to mechanical loading potentially affects bone mass. This paradigm could have implications for the field of rheumatology, where proinflammatory cytokines might affect bone mass by altering the response of osteocytes to mechanical loading.