Inflammatory Processes Affecting Bone Health and Repair

Abstract

Purpose of Review

The purpose of this article is to review the current understanding of inflammatory processes on bone, including direct impacts of inflammatory factors on bone cells, the effect of senescence on inflamed bone, and the critical role of inflammation in bone pain and healing.

Recent Findings

Advances in osteoimmunology have provided new perspectives on inflammatory bone loss in recent years. Characterization of so-called inflammatory osteoclasts has revealed insights into physiological and pathological bone loss. The identification of inflammation-associated senescent markers in bone cells indicates that therapies that reduce senescent cell burden may reverse bone loss caused by inflammatory processes. Finally, novel studies have refined the role of inflammation in bone healing, including cross talk between nerves and bone cells.

Summary

Except for the initial stages of fracture healing, inflammation has predominately negative effects on bone and increases fracture risk. Eliminating senescent cells, priming the osteo-immune axis in bone cells, and alleviating pro-inflammatory cytokine burden may ameliorate the negative effects of inflammation on bone.

Introduction

Osteoporosis is an enormous public health burden that affects men and women of all races. About 50% of women and 20% of men in the USA over the age of 50 years will experience an osteoporotic fracture [1]. Osteoporosis is characterized by bone mineral density (BMD) at the hip or lumbar spine that is ≤ 2.5 standard deviations below the mean BMD of a reference population of young adults. The main features of osteoporosis are low bone density, disrupted bone microarchitecture, compromised bone strength, and fracture [1]. Despite effective pharmacological interventions, osteoporosis remains underdiagnosed and undertreated. The osteoporosis treatment gap (defined as the difference between the number of patients that meet treatment indications and the number that receive treatment) is a crisis in patient care worldwide [2, 3]. It is crucial to identify and understand underlying diseases and physiological processes that may contribute to osteoporosis, including inflammation.

Inflammation is the body’s response to pathogens or tissue damage. During an inflammatory response, cells of the innate and adaptive immune systems are recruited and activated by cytokines, such as interferons, interleukins, and chemokines. These inflammatory factors have a direct effect on the differentiation and function of multiple bone cell types, including osteoblasts, osteoclasts, and osteocytes [4, 5]. Many diseases can lead to inflammatory bone loss, including inflammatory bowel disease, spondyloarthritis, systemic lupus erythematosus, and chronic obstructive pulmonary disease, among others [6]. Anti-inflammatory medications can also induce bone loss, most notably glucocorticoids. In recent years, the field of osteoimmunology has developed new techniques and models to interrogate inflammatory processes in the bone. From these discoveries, therapies targeted at blocking cytokine activity and depleting or inhibiting aberrant immune responses are in development to improve bone density and reduce fracture risk [4, 7–9]. However, it is important not to eliminate all inflammation from the bone microenvironment, as inflammatory processes are crucial for early stages of bone healing and repair.

Inflammation is Critical in Bone Healing

While inflammation is largely associated with negative outcomes on bone, inflammatory processes are also essential for maintaining bone health. Bone healing following fracture takes place in three overlapping phases: the inflammatory phase, the repair phase, and the remodeling phase [10]. Complete healing of the injury is critically dependent on success of the initial inflammatory phase. Acute inflammation following injury peaks within the first 24–48 hours and is generally complete by 7 days. In response to fracture, blood vessels rupture within and around the fracture site, inducing a hematoma. The hematoma is a scaffold for infiltrating macrophages (osteomacs), lymphocytes, fibroblasts, and mast cells, which release pro-inflammatory cytokines (e.g., interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α), chemokines, and growth factors [11, 12]. Polymorphonuclear neutrophils and M1-polarized macrophages in this first wave of immune infiltration clear away dead cells and debris. To resolve the initial acute inflammation and allow for the next phases of repair, macrophages polarize from an M1 to an M2 phenotype following stimulation by anti-inflammatory cytokines, including IL-4 and IL-10, while mesenchymal progenitor cells are attracted to the site of injury by TNF-α and CXCL12. This cocktail of pro- and anti-inflammatory cytokines, along with growth factors (TGF-β) and bone morphogenic proteins (BMPs), initiates angiogenesis and osteogensis to form a soft callus. Pro-inflammatory cytokines are more lowly expressed during the repair phase, when the hard callus is formed, but are elevated again during the remodeling phase, when bone is restored to its original shape, structure, and mechanical integrity. Inhibiting inflammatory cytokines such as IL-6 or TNF-α delays fracture healing [13, 14]. Additionally, prolonged use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a higher risk of bone nonunions and delayed unions [15, 16]. These and other studies highlight the critical role of inflammatory mediators in effective bone healing.

During the inflammatory phase of fracture repair, mesenchymal progenitors are recruited from both the periosteum and the bone marrow to the injury [17]. Periosteal progenitor cells are influenced by the inflammatory milieu [18, 19]. For example, inflammation associated with aging alters effective recruitment and differentiation of periosteal progenitors, delaying bone healing post-fracture [20]. Aged human periosteal progenitors are less proliferative and produce more IL-6 and other inflammatory cytokines than progenitors from younger subjects [21]. In mouse models, progenitor cells from old mice create a pro-inflammatory, degenerative niche that limits effective fracture healing [20]. Bone healing demonstrates that numerous cell types at various stages of differentiation in the microenvironment are all potential targets of inflammatory processes.

The Effects of Inflammation on Bone Cells

Bone Remodeling and the RANK-RANKL-OPG Axis

Inflammatory processes cause bone loss by uncoupling bone formation from resorption. Osteoblasts form bone and couple with bone-resorbing osteoclasts [22] by secreting two cytokines: macrophage colony stimulating factor (M-CSF) and receptor activator of NF-κB (RANK) ligand (RANKL). Osteocytes embedded in the bone matrix are also major producers of RANKL [23]. Upon stimulation with M-CSF and RANKL, myeloid progenitor cells expressing Csf1r (the receptor for M-CSF) and RANK (the receptor for RANKL) activate transcription factors including c-Fos, NF-κB, and NFATc1 to induce osteoclast differentiation. Osteoprotegerin (OPG) is also secreted by osteoblasts and is a soluble decoy receptor for RANKL, antagonizing RANK signaling. RANKL signaling is a potent inducer of osteoclast activity and induces bone loss. The FDA-approved therapeutic denosumab is a monoclonal antibody against RANKL and suppresses osteoclastogenesis to prevent excessive bone resorption [24].

RANK-RANKL signaling is at the crux of osteoimmunology. In addition to regulating osteoclastogenesis in the bone, RANK-RANKL signaling controls maturation and functioning of the thymus, bone marrow, and lymph nodes. In bone, various pro-inflammatory cytokines, including IL-6, IL-17, and TNF-α, induce RANK-RANKL signaling to drive osteoclastic resorption and bone loss [25].

Osteoclasts are the Main Targets of Inflammatory Processes in Bone

Osteoclasts are the main targets of inflammatory processes in the bone microenvironment (Fig. 1) [26]. Osteoclasts are bone-resorbing cells that derive from the monocyte/macrophage lineage following stimulation by M-CSF and RANKL [27, 28]. In inflammatory conditions [29], osteoclasts can arise from other precursors, including inflammatory dendritic cells [30, 31] or arthritis-associated osteoclastogenic macrophages (AtoMs) [32, 33]. Inflammatory cytokines such as TNF-α [34–38], IL-1 [39–42], IL-6 [43, 44], IL-7 [45–47], and IL-17 [48–51] induce osteoclast maturation and activity. TNF-α is particularly important in regulating bone resorption and can induce inflammatory osteoclast differentiation independent of the canonical RANKL pathway, ultimately resulting in bone loss [38, 52]. Osteoclastic response to inflammation is sexually dimorphic, with pre-osteoclasts derived from female mice showing enhanced inflammatory pathway activation compared to male pre-osteoclasts [53].

Fig. 1.

Physiological versus pathological osteoclast maturation and activity. Under normal physiological conditions, osteoclasts work in balance with osteoblasts and osteocytes to remodel bone. Under pathological inflammatory conditions, osteoclasts are derived from multiple sources and aberrantly activated, inducing bone loss. AtOM, arthritis-associated osteoclastogenic macrophages; SASP, senescence-associated secretory phenotype. Figure created with http://Biorender.com.

In human and murine bone, osteoclasts form either pits (round holes in the bone surface) or trenches (formed by osteoclasts migrating across the bone surface while resorbing) [54, 55]. Bone from osteoporotic patients shows a high prevalence of trenches [56], which are correlated with impaired bone strength [57]. Glucocorticoids increase trench formation in human and rabbit bone [57–59].

While excessive osteoclast activity induces pathological bone loss, basal osteoclastogenesis and bone resorption is a crucial component of healthy bone remodeling [60, 61]. Inflammatory osteoclast precursors (Ly6C^hiCD11b^hi) expand during chronic inflammation and generate more active osteoclasts. These inflammatory osteoclast precursors are regulated by TNF-α, as they were rendered ineffective in tnf-α^−/− mice [62••]. Mature osteoclasts are also regulated by inflammation. Pathologically activated osteoclasts (PAOCs) have significant proton secretion and motility, leading to a high degree of bone resorption in the presence of IL-1β [41]. Recently, a new class of inflammatory osteoclasts (iOCs) were characterized as Cx3cr1 negative (Cx3cr1^neg) or positive (Cx3cr1⁺). Cx3cr1^neg iOCs potently resorb bone, produce pro-inflammatory cytokines, and activate inflammatory bone marrow CD4⁺ T cells. By contrast, Cx3cr1⁺ iOCs have an immune-suppressive effect on Cx3cr1^neg iOCs in culture [30, 63••, 64]. Identifying classes of inflammatory pre-osteoclasts or osteoclasts is an essential step in developing new therapeutics targeted at only pathologically active, inflammatory osteoclasts [65•].

Osteoblasts and Osteocytes are Regulated by Inflammatory Signaling

Inflammatory mediators directly and indirectly suppress osteoblast activity to prevent bone formation [4]. In addition to producing RANKL and OPG, which agonize and antagonize, respectively, the RANK signaling cascade, osteoblasts produce pro-inflammatory cytokines [66–68]. Cytokines, including IL-6, IL-7, IL-17, and TNF-α, stimulate secretion of RANKL from osteoblasts [69]. Cytokines can also inhibit osteoblasts through mechanisms independent of RANKL. For example, TNF-α inhibits osteoblastogenesis [70–72] by repressing Runx2, the master transcription factor regulating osteoblast maturation [73]. TNF-α also induces the expression of Dickkopf-1 (DKK1), inhibiting Wnt signaling that is crucial for osteoblastogenesis [74]. IL-1β impairs osteoblast migration, potentially impairing osteoblast recruitment during early stages of fracture healing [75].

While inflammatory cytokines generally favor bone resorption resulting in bone loss, certain cytokines are osteoblastogenic [9]. For example, while IL-11 was originally characterized pro-osteoclastic [76], more recent reports indicate that IL-11 enhances osteogenesis [77]. IL-11^−/− mice have low bone mass due to suppressed osteoblast activity [78, 79]. IL-10^−/− mice also have low bone mass [80], as IL-10 induces osteogenesis [81, 82] and inhibits bone resorption [83]. IFN-γ promotes osteoblast differentiation from mesenchymal progenitors [84] and reverses osteoporosis in ovariectomized mice [85] but was shown to stimulate bone loss in vivo [86]. Finally, although the main role of IL-6 is to induce osteoclastogenesis and stimulate bone resorption [87], IL-6 stimulates mesenchymal progenitor cell differentiation towards osteoblasts [88] and can stimulate bone formation in vivo in the presence of a soluble IL-6 receptor [89].

Osteocytes are terminally differentiated osteoblasts and are the most abundant and longest-living cell type in bone [90]. Osteocytes are the main mechanosensing cell in bone and coordinate the action of osteoblasts and osteoclasts on bone surfaces [91–93]. Through a process called perilacunar/canalicular remodeling, osteocytes can also resorb their surrounding matrix. Glucocorticoids suppress normal perilacunar remodeling, causing bone degeneration [94]. Osteocytes express pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α [95], which in turn enhance osteocyte RANKL expression, inducing osteoclastogenesis and bone loss [34, 96, 97]. In animal models of periodontitis [98, 99] and inflammatory bowel disease [100], the number of osteocytes expressing RANKL is increased along with greater osteoclast activity. Due to their mechanosensing properties, osteocytes may play a particularly significant role in regulating the inflammatory response to periodontal disease because alveolar surfaces on teeth are under consistent mechanical stress [99]. All bone cells, including osteoclasts, osteoblasts, and osteocytes, are susceptible to the effects of inflammation, highlighting why so many diseases are associated with inflammatory bone loss.

Diseases and Therapeutics Associated with Inflammatory Bone Loss

Chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease (IBD) (e.g., Crohn’s disease and ulcerative colitis), and periodontitis are frequently associated with low BMD [6]. Inflammation also drives bone loss in cystic fibrosis [101], ankylosing spondylitis [102], chronic obstructive pulmonary disease [103], systemic lupus erythematosus [104], and psoriasis [105] (Table 1). Chronic, systemic inflammation characteristic of these diseases increases the risk of fracture.

Table 1.

Inflammatory diseases and therapeutics comorbid with bone loss.

Disease / therapeutic	Type of bone loss	References
Ankylosing spondylitis	Systemic	(90)
Chronic obstructive pulmonary disease	Systemic	(91)
Cystic fibrosis	Systemic	(89)
Glucocorticoids	Systemic	(48, 49, 99, 136–139, 172)
Inflammatory bowel disease & gut dysbiosis	Systemic	(122–128)
Periodontitis	Systemic, local (alveolar)	(7, 20, 86, 87, 129–135, 165)
Postmenopausal osteoporosis	Systemic	(109–116)
Psoriasis	Systemic	(93)
Rheumatoid arthritis	Systemic, local (focal / periarticular)	(20, 117–121)
Systemic lupus erythematosus	Systemic	(92)

Inflammation in Fracture Risk and Bone Mechanical Strength

The central concern associated with inflammatory bone loss is increased susceptibility to fracture. Mechanical integrity of the bone plays a key role in determining the risk of fracture and severity of injury. In addition to the direct effects of inflammatory mediators on bone cells, chronic inflammatory conditions are also associated with immobility, poor nutrition, and low exercise tolerance, which can themselves lead to bone loss [6]. Inflammatory bone loss is associated with an increased fracture risk [4], which is correlated with altered BMD [106], increased cortical porosity [107], and disruption of various architectural components of bone [108, 109]. Using any one measure to assess bone quality and fracture risk is a challenge due to the complex and dynamic nature of bone. As such, none of these measures alone can completely account for fracture risk in inflammatory bone conditions. Recently, more comprehensive measures such as Trabecular Bone Score are improving patient monitoring in multiple inflammation-based chronic conditions including ankylosing spondylitis and glucocorticoid-induced osteoporosis [110–113].

Chronic, low-grade inflammation is also associated with aging, so-called inflammaging [114]. In the elderly, fractures are frequent and heal slowly, with more nonunions than young populations [115]. Aged macrophages are more sensitive to inflammatory signals and fail to resolve from the M1 to the M2 phenotype, delaying healing after fracture [116]. In addition, age-related inflammation mediated by NF-κB and TLR signaling reduces the number and function of skeletal progenitor cells, compromising regenerative processes needed for fracture repair [117–119]. Recent work has examined the therapeutic potential of optimizing the inflammatory stage of bone healing to prevent impaired fracture healing (e.g., hypertrophic or atrophic nonunions) [10, 114].

Despite the correlation between chronic inflammatory conditions and increased fracture risk, the effects of inflammation on the mechanical integrity of the bone vary significantly. For example, osteoporosis and type 2 diabetes mellitus patients have increased fracture risk. However, while osteoporosis reduces BMD, patients with type 2 diabetes may have normal or even high volumetric BMD, despite suppressed bone formation [120]. These data indicate that different inflammatory conditions alter bone quality through distinct pathways and therefore cannot be monitored or assessed using the same standard measures.

Postmenopausal Osteoporosis

Following menopause, a sharp drop in estrogen levels causes the rate of bone resorption to exceed that of bone formation, resulting in net bone loss. As such, postmenopausal women are at significant risk for osteoporosis [121]. Estrogen inhibits the production of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-17 by immune cells, including B cells, T cells, and macrophages [122]. Increased levels of pro-inflammatory cytokines in the serum are associated with low BMD and elevated fracture risk in postmenopausal women [123–126]. Reducing systemic inflammation may be considered therapeutic for postmenopausal women. Administration of IL-1β (anakinra) or TNF-α (etanercept) inhibitors following acute estrogen withdrawal in postmenopausal women suppressed the normal rise in bone resorption markers in the serum [127].

Estrogen coordinates multiple organ systems that cross talk to maintain bone. For example, estrogen decline and bone loss in ovariectomized mice induces chronic low-grade inflammation (including elevated IL-17 and TNF-α) mediated by dendritic cell activation of memory T cells via IL-7 and IL-15. Ablating IL15RA in T cells prevented elevations in IL-17 and TNF-α and reversed the ovariectomy-induced bone loss [128••]. These and other studies suggest that the pro-inflammatory immune status of postmenopausal women likely contributes to the direct effects of estrogen withdrawal on bone cells to drive bone loss [122].

Rheumatoid Arthritis

Rheumatoid arthritis stimulates both local (focal or periarticular) and systemic bone loss [129, 130]. Osteitis (inflammation within the bone) is evident in patients with rheumatoid arthritis via MRI and can be used as a predictor for rheumatoid arthritis prognosis and progression [131]. Inflammation in the joint of rheumatic patients involves all compartments, including the synovial membrane, cartilage, and subchondral bone. Osteoporosis and rheumatoid arthritis severity is correlated with circulating levels of IL-6, IL-10, and C-reactive protein (CRP), indicating that local joint inflammation may drive systemic inflammation and bone loss [132]. Several current therapies for rheumatoid arthritis target pro-inflammatory cytokines such as TNF-α or block cytokine-mediated activation of the Janus kinases (JAK)–signal transducer and activator of transcription (STAT) signaling pathways [133].

Inflammatory Bowel Disease

Intestinal inflammation characteristic of IBD induces bone loss through secretion of pro-inflammatory cytokines including IL-1, IL-6, and TNF-α. Patients (particularly postmenopausal patients) with IBD are at risk for osteoporosis and fracture, primarily due to insufficient calcium, vitamin D, and vitamin K absorption [134]. The intestinal microbiota is also disrupted in IBD, which can lead to inflammatory bone loss [135–137]. For example, deletion of toll-like receptor 9 (TLR9) alters the gut microbiota to induce low-grade chronic inflammation and bone resorption [138]. New therapies for osteoporosis based on modulation of the gut microbiota and the immuno-inflammatory response are under investigation, including modulation of T helper 17 (T_h17) cells [139, 140].

Periodontitis

Periodontitis is inflammation of the tissue around the teeth and is associated with both local (alveolar) and systemic bone loss, as well as fracture [4, 141, 142]. Upon bacterial infection, there is sustained production of pro-inflammatory cytokines, causing a local immune reaction that stimulates osteoclastogenesis. Recent single-cell RNA sequencing experiments showed that, in response to acute inflammation, periodontal mesenchymal progenitor cells differentiate into osteoblasts, presumably to balance the osteoclastogenic response to inflammation [143••]. Ultimately, sustained periodontal inflammation causes lesions in the bone that painfully expose tooth roots and cause tooth loss. Like rheumatoid arthritis and IBD, patients with periodontitis have elevated serum levels of various pro-inflammatory factors, including TNF-α, IL-1, and IL-6 [144]. Recruiting regulatory T cells (Tregs) to the site of inflammation prevents periodontal bone loss in both murine and canine models [145].

In periodontitis and other chronic conditions, inflammation may be the key mechanistic link between the tissue-specific disease and systemic bone loss [146]. This is exemplified by a study in which inducing periodontitis in mice caused epigenetic changes to hematopoietic progenitor cells in the bone marrow as well as production of myeloid cells. Transplanting the periodontitis-induced bone marrow to naïve recipients increased the recipients’ inflammatory response and the disease severity of induced inflammatory arthritis [147••]. Therefore, an immune system “trained” to respond to inflammatory cues may predispose individuals to inflammatory comorbidities, including bone loss.

Glucocorticoids

Glucocorticoids reduce inflammation and are primary drugs for treatment of chronic inflammatory diseases, including those that induce bone loss. Ironically, glucocorticoid-induced osteoporosis is common and is associated with fracture risk in a dose-dependent manner [148]. Glucocorticoids both inhibit bone formation and stimulate bone resorption, with direct effects on osteoclasts, osteoblasts, and osteocytes [149]. Careful monitoring of patients using glucocorticoids with high fracture risk is warranted and usually necessitates co-treatment with anti-osteoporotic drugs, such as bisphosphonates [150, 151].

Inflammation in Bone Pain

In addition to increasing risk of fracture, inflammatory processes can also induce bone pain, significantly affecting quality of life. The periosteum, bone marrow, and the Haversian canals of cortical bone are highly innervated with sensory and sympathetic nerve fibers of the peripheral nervous system (PNS) that influence bone homeostasis and are sensitive to inflammatory stimuli [152, 153]. Two major ascending (or afferent) routes relay signals from the PNS to the central nervous system. The first consists of somatosensory neurons in the dorsal root ganglia that signal from the skeleton, skin, or muscle to the brain via the dorsal horn of the spinal cord about temperature, pain, and injury [154]. The second route consists of sensory ganglia that receive peripheral sensory stimuli in the cranial and vagal pathways. Afferent sensory nerve endings within the skeleton are responsible for detecting and transmitting the quality of pain to the brain.

During skeletal stress (i.e., mechanical distortion, local acidosis produced by proton release from osteoclasts and inflammatory cells, or an increase in intramedullary pressure), osteoblasts, osteoclasts, and immune cells produce growth factors and inflammatory mediators that affect sensory neuron activation, sprouting, and neuropeptide release. Activated small- and medium-sized neurons release neurotransmitters that act on skeletal cells such as osteoblasts, osteoclasts, and bone marrow adipocytes [155]. The release of these mediators at the site of stress can sensitize nerve endings, making Aδ-fibers and C-fibers easier to depolarize and thus highly sensitive to nociceptive stimuli [156]. Inflammatory mediators such as histamine, serotonin, bradykinin, and prostaglandin E2 can also cause sensitization of nociceptor sensory nerve endings [157–159]. While excessive pain profoundly affects quality of life, pain is also crucially important to alert the body of injury or disease. In this way, inflammatory signaling in bone serves an essential role to maintain overall health.

New Targets for Alleviating Inflammatory Bone Loss

Modulation of the Osteo-immune Axis

Tissue engineering strategies are leveraging the osteo-immune axis to resolve chronic bone loss and enhance bone healing. Various efforts in skeletal regenerative medicine are targeted at modulating mesenchymal progenitor cells (MPC) [160–162]. Application of MPCs from various sources, including adipose tissue, bone marrow, or dental pulp, aids in fracture repair in part by inhibiting chronic inflammation [162]. Pre-conditioning MPCs with inflammatory stimuli can enhance their osteogenic capabilities [10]. MPCs hold great promise in orthopedic therapies, but their success has been limited thus far in clinical trials. Improving MPC survival and response to a harsh inflammatory environment is key to their use in future clinical applications to aid bone healing or prevent bone loss [160].

Additional efforts are targeted at modulating the osteo-immune axis by delivering anti-inflammatory cytokines. Anti-inflammatory cytokines such as IL-4 prevent bone loss and accelerate bone formation in animal models of chronic inflammation and bone healing by polarizing macrophages to the M2 phenotype [163–166]. The method of releasing these cytokines in the local bone environment, for example, in accelerating or aiding healing following fracture, is dependent on multiple factors. The appropriate scaffold must be used, taking into consideration the timing, dose, and duration of release [167, 168]. In addition, the appropriate cytokine or combination of cytokines must be considered. For example, IL-10 is generally considered pro-osteogenic at low concentrations, whereas higher concentrations of IL-10 have been shown to inhibit osteogenesis [81]. Additionally, circulating levels of IL-10 are negatively correlated with bone regeneration following traumatic orthopedic injury [169]. These results highlight that the concentration, timing, and type of injury all need to be considered when targeting the inflammatory axis to maintain bone health.

Alleviating Cellular Senescence-Induced Inflammation

One of the hallmarks of cellular senescence is production of inflammatory factors [170]. Senescent cells are beneficial in normal physiological functions, such as wound healing, when senescent cells attract and activate immune cells to initiate tissue remodeling [171]. However, chronic senescent cell accumulation contributes to a variety of pathologies across the lifespan, and particularly in aging [170]. Accumulation of senescent cells during aging is, in part, attributable to impaired surveillance of immune cells and chronic systemic inflammation [172]. Classic features of senescent cells include enlarged and flattened cell morphology, highly condensed chromatin, growth arrest, resistance to apoptosis, and development of a senescence-associated secretory phenotype (SASP). The SASP is composed of pro-inflammatory cytokines, chemokines, growth factors, and matrix-degrading proteases, and its release has a profound effect on the local environment surrounding the senescent cell.

Senescent cells induce local and systemic pro-inflammatory reactions that negatively impact bone [173]. Senescent cells and their associated SASP factors are present in the bone microenvironment of old mice [174], and reducing the systemic senescent cell burden prevents age-related bone loss [175, 176]. In an aged murine model of periodontal disease, senescent osteocytes exacerbate chronic inflammation, suppressing alveolar bone regeneration [177••]. Osteocyte senescence is also implicated in diabetic bone loss [178] and focal bone loss following radiation [179] in rodent models. Senescent osteocytes in aged human bone tissue induce inflammation that inhibits bone formation [180•].

Inflammatory senescence has negative effects on young bone as well. Glucocorticoids are widely prescribed for chronic inflammatory childhood illnesses, and glucocorticoid-induced osteoporosis is the most common form of secondary pediatric osteoporosis [181]. Glucocorticoid treatment of young mice induces vascular endothelial cell senescence in the metaphysis of long bone, and inhibiting this senescence improves angiogenesis and osteogenesis [182]. Glucocorticoids also induce senescence of adult bone marrow adipocytes, causing secondary senescence in surrounding bone tissue and inducing bone loss [183]. Eliminating senescent cells systemically [184] or in bone marrow adipocytes [183] prevents glucocorticoid-induced bone loss. Clearing transient senescent cells that accumulate following fracture also improves bone healing [185].

Conclusions

Inflammatory processes play a critical role in regulating bone homeostasis and disease. Systemic bone loss induced by inflammatory diseases, including rheumatoid arthritis, IBD, and periodontitis, contributes significantly to the worldwide osteoporosis crisis. While pro-inflammatory cytokines such as TNF-α and IL-1 have largely negative effects, inducing aberrant osteoclastogenesis and bone loss, pro-osteogenic cytokines such as IL-4 and IL-11 target osteoblasts to induce osteogenesis. New advances in osteoimmunology have isolated subtypes of bone cells that are the major players in inflammatory bone loss, including inflammatory osteoclasts and senescent osteocytes. Identification of inflammation-specific processes is crucial to identify therapies that can improve pathological inflammatory bone loss, while maintaining physiological bone turnover.