Therapeutic effect of NLRP3 inhibition on hearing loss induced by systemic inflammation in a CAPS-associated mouse model.

BACKGROUND: Cryopyrin-associated periodic syndrome (CAPS) is an inherited autoinflammatory disease caused by a gain-of-function mutation in NLRP3. Although CAPS patients frequently suffer from sensorineural hearing loss, it remains unclear whether CAPS-associated mutation in NLRP3 is associated with the progression of hearing loss. METHODS: We generated a mice with conditional expression of CAPS-associated NLRP3 mutant (D301N) in cochlea-resident CX3CR1 macrophages and examined the susceptibility of CAPS mice to inflammation-mediated hearing loss in a local and systemic inflammation context. FINDINGS: Upon lipopolysaccharide (LPS) injection into middle ear cavity, NLRP3 mutant mice exhibited severe cochlear inflammation, inflammasome activation and hearing loss. However, this middle ear injection model induced a considerable hearing loss in control mice and inevitably caused an inflammation-independent hearing loss possibly due to ear tissue damages by injection procedure. Subsequently, we optimized a systemic LPS injection model, which induced a significant hearing loss in NLRP3 mutant mice but not in control mice. Peripheral inflammation induced by a repetitive low dose of LPS injection caused a blood-labyrinth barrier disruption, macrophage infiltration into cochlea and cochlear inflammasome activation in an NLRP3-dependent manner. Interestingly, both cochlea-infiltrating and -resident macrophages contribute to peripheral inflammation-mediated hearing loss of CAPS mice. Furthermore, NLRP3-specific inhibitor, MCC950, as well as an interleukin-1 receptor antagonist significantly alleviated systemic LPS-induced hearing loss and inflammatory phenotypes in NLRP3 mutant mice. INTERPRETATION: Our findings reveal that CAPS-associated NLRP3 mutation is critical for peripheral inflammation-induced hearing loss in our CAPS mice model, and an NLRP3-specific inhibitor can be used to treat inflammation-mediated sensorineural hearing loss. FUNDING: National Research Foundation of Korea Grant funded by the Korean Government and the Team Science Award of Yonsei University College of Medicine.

The Clinical Application of Pulsed Radiofrequency Induces Inflammatory Pain via MAPKs Activation: A Novel Hint for Pulsed Radiofrequency Treatment.

Pulsed radiofrequency (PRF) works by delivering short bursts of radiofrequency to a target nerve, thereby affecting nerve signal transduction to reduce pain. Although preliminary clinical investigations have shown that PRF treatment can be used safely as an alternative interventional treatment in patients with refractory pain conditions, unexpected damage to a normal nerve/ganglion is still one of the possible complications of using the PRF strategy. Noxious pain may also be triggered if PRF treatment accidentally damages an intact nerve. However, few studies in the literature have described the intracellular modifications that occur in neuronal cells after PRF stimulation. Therefore, in this study, we evaluated the effects of PRF on unimpaired nerve function and investigated the potential mechanisms of PRF-induced pain. Wistar rats were stimulated with 30-60 V of PRF for 6 min, and mechanical allodynia, cold hypersensitivity, cytokine and matrix metalloproteinase (MMP) production, and mitogen-activated protein kinase activity (p38 MAPK, ERK1/2, JNK/SAPK) were analyzed. The results indicated that PRF stimulation induced a significant algesic effect and nociceptive response. In addition, the protein array and Western blotting analyses showed that the clinical application of 60 V of PRF can induce the activation of MAPKs and the production of inflammatory cytokines and MMPs in the lumbar dorsal horn, which is necessary for nerve inflammation, and it can be suppressed by MAPK antagonist treatment. These results indicate that PRF stimulation may induce inflammation of the intact nerve, which in turn causes inflammatory pain. This conclusion can also serve as a reminder for PRF treatment of refractory pain.

Validity and reliability of the Turkish version of the Cold Intolerance Symptom Severity Questionnaire

Background/aim: The aim of this study was to determine validity and reliability of the Turkish version of the Cold Intolerance Symptom Severity (CISS-T) Questionnaire. Materials and methods: The translation and back translation steps of the study were based on the Beaton guidelines. Sixty-eight patients between 18 and 65 years old with cold intolerance after amputation, replantation, multiple crush syndrome, and peripheral nerve injury were included in the study. Patients completed the Disabilities of the Arm, Shoulder, and Hand Questionnaire (DASH), the SF-36 Quality of Life Questionnaire, and the single questions assessing the cold sensitivity and cold intolerance once and the final version of the CISS-T twice with a 7-day interval. Results: The internal consistency (Cronbach α = 0.844) and test-retest reliability (r = 0.938) of CISS-T were assessed and both were considerably high. Also, the correlations between the scores of the CISS-T, DASH-T, SF-36-T, and the single questions were analyzed by Spearman's correlation coefficient. The CISS-T showed an excellent correlation with the single questions (rho = 0.8 and 0.877), a good and negative correlation with the pain subscale of the SF-36 (rho = 0.617), and a moderate correlation with the DASH-T (rho = 0.592). Conclusion: As a result, the CISS-T is a valid and reliable instrument to assess the severity of cold intolerance.

Cold hypersensitivity after hand injuries. A prospective 7-year follow-up.

We studied changes in cold hypersensitivity from 3 to 7 years following severe hand injuries. Data was collected using postal questionnaires 7 years after injury in 71 patients who had participated in a 3-year follow-up from the time of injury. There was no change in cold sensitivity measured using the McCabe Cold Sensitivity Severity scale (CSS) from 3 to 7 years after injury. However, there was a trend toward decreased severity measured using a five-level scale of self-reported cold hypersensitivity. Compared to the 3-year follow-up, fewer respondents rated their condition as severe and two patients had recovered from their cold hypersensitivity at the 7-year follow-up. Furthermore, 21 (30%) of the respondents stated a decrease in cold hypersensitivity during the last 2 years. Limitations in cold associated activities and the importance of being less limited in leisure activities (NRS 0-10) did not change between the two follow-ups. In conclusion, the CSS-scores did not change from 3 to 7 years after injury. Several patients experienced improvements in cold hypersensitivity, but few recovered completely from the condition.

TRPA1 sensitization during diabetic vascular impairment contributes to cold hypersensitivity in a mouse model of painful diabetic peripheral neuropathy.

Background Diabetic peripheral neuropathy is a common long-term complication of diabetes. Accumulating evidence suggests that vascular impairment plays important roles in the pathogenesis of diabetic peripheral neuropathy, while the mechanism remains unclear. We recently reported that transient receptor potential ankyrin 1 (TRPA1) is sensitized by hypoxia, which can contribute to cold hypersensitivity. In this study, we investigated the involvement of TRPA1 and vascular impairment in painful diabetic peripheral neuropathy using streptozotocin-induced diabetic model mice. Results Streptozotocin-induced diabetic model mice showed mechanical and cold hypersensitivity with a peak at two weeks after the streptozotocin administration, which were likely to be paralleled with the decrease in the skin blood flow of the hindpaw. Streptozotocin-induced cold hypersensitivity was significantly inhibited by an antagonist HC-030031 (100 mg/kg) or deficiency for TRPA1, whereas mechanical hypersensitivity was unaltered. Consistent with these results, the nocifensive behaviors evoked by an intraplantar injection of the TRPA1 agonist allyl isothiocyanate (AITC) were enhanced two weeks after the streptozotocin administration. Both streptozotocin-induced cold hypersensitivity and the enhanced AITC-evoked nocifensive behaviors were significantly inhibited by a vasodilator, tadalafil (10 mg/kg), with recovery of the decreased skin blood flow. Similarly, in a mouse model of hindlimb ischemia induced by the ligation of the external iliac artery, AITC-evoked nocifensive behaviors were significantly enhanced three and seven days after the ischemic operation, whereas mechanical hypersensitivity was unaltered in TRPA1-knockout mice. However, no difference was observed between wild-type and TRPA1-knockout mice in the hyposensitivity for current or mechanical stimulation or the deceased density of intraepidermal nerve fibers eight weeks after the streptozotocin administration. Conclusion These results suggest that TRPA1 sensitization during diabetic vascular impairment causes cold, but not mechanical, hypersensitivity in the early painful phase of diabetic peripheral neuropathy. However, TRPA1 may play little or no role in the progression of diabetic peripheral neuropathy.

IL-1ß Enhances Wnt Signal by Inhibiting DKK1.

Aberrant endochondral bone formation in the physis is a unique bone lesion in neonatal-onset multisystem inflammatory disease (NOMID), also called chronic infantile neurologic cutaneous articular (CINCA), the most severe of the cryopyrin-associated periodic syndrome (CAPS) diseases, which are interleukin-1ß (IL-1ß)-related monogenic autoinflammatory diseases. The wingless (Wnt) pathway plays an important role in osteoblast differentiation. In this study, we explored the potential role of IL-1ß on the expression of WNT genes and the Wnt antagonist Dickkopf-1 (DKK1). The expression of WNT and DKK1 in fibroblast-like synoviocytes (FLS), which are articular resident cells, was quantified by quantitative PCR and enzyme-linked immunosorbent assay. Additionally, we used T cell factor (TCF) reporter assays to evaluate the activity of the canonical Wnt signal pathway in the presence or absence of the supernatant of cultured FLS treated with or without IL-1ß and IL-6. Anti-DKK1 antibodies were used to neutralize DKK1. The expression of both canonical and non-canonical WNT genes as well as DKK1 was observed in FLS. The supernatant of cultured FLS suppressed the luciferase activity of the TCF reporter, and this effect was reduced by its pre-treatment with an anti-DKK1 antibody. Both IL-1ß and IL-6 significantly reduced DKK1 production. Furthermore, the supernatant of FLS cultured with IL-1ß or IL-6 showed a reduced inhibitory effect on Wnt signaling, compared with the supernatant of untreated FLS. These data suggest that IL-1ß, like IL-6, dampens DKK1 production, and thereby promotes Wnt signal activation. Therefore, increased levels of IL-1ß may contribute to the dysregulation of endochondral ossification in NOMID/CINCA.

An unusual hazard of menopause in the workplace: a case report.

Untreated vasomotor symptoms of the menopause can have a major impact on women at work. Recent recommendations advocate modification of the working environment, including adequate air-conditioning, to help relieve these symptoms. However, this may cause discomfort for work colleagues. We report the case of a 40-year-old woman with cold urticaria. Cold urticaria is a serious, potentially life-threatening condition. Our patient's symptoms were exacerbated when her postmenopausal work colleagues turned the air-conditioner temperature down to relieve their vasomotor symptoms.

Unusual case of hypotenar Hammer Syndrome and carpal tunnel syndrome association.

BACKGROUND AND AIM OF THE WORK: Hypothenar Hammer Syndrome is a relatively rare disease process caused by repetitive stress or injury to the hypothenar eminence leading to chronic injury to the ulnar artery. Our study reports an unusual case. METHODS: A 57 years old Plumber presented in April 2016 with a history of constant pain and recurrent paresthesia involving the fingers of the right hand for several months, over the previous 1 year, his hand had become more intolerant of exposure to cold temperatures. Angio-RNM and electromyography were performed and showed a severe double compression of ulnar and median nerve and an ulnar artery deformity without thrombosis. Surgery was performed under sedation and axillary anesthesia. RESULTS: After surgery patient' symptoms immediately improved, and within a few months, his hand had normalized. CONCLUSION: Hypothenar Hammer Syndrome is a rare disease process which manifests in certain occupations and activities that put undue stress on the hypothenar area. Furthermore, the carpal tunnel syndrome, a pressure damage of the median nerve, caused by repetitive manual tasks with flexion and extension of wrist has been added as well as hypothenar hammer syndrome which are vascular damages of hand caused by shock-type application of force.

Brain activity changes in a macaque model of oxaliplatin-induced neuropathic cold hypersensitivity.

The antineoplastic agent oxaliplatin induces a painful peripheral neuropathy characterized by an acute cold hypersensitivity. There is a lack of effective treatments to manage oxaliplatin-induced cold hypersensitivity which is due, in part, to a lack of understanding of the pathophysiology of oxaliplatin-induced cold hypersensitivity. Thus, brain activity in oxaliplatin-treated macaques was examined using functional magnetic resonance imaging (fMRI). Oxaliplatin treatment reduced tail withdrawal latency to a cold (10 °C) stimulus, indicating cold hypersensitivity and increased activation in the secondary somatosensory cortex (SII) and the anterior insular cortex (Ins) was observed. By contrast, no activation was observed in these areas following cold stimulation in untreated macaques. Systemic treatment with an antinociceptive dose of the serotonergic-noradrenergic reuptake inhibitor duloxetine decreased SII and Ins activity. Pharmacological inactivation of SII and Ins activity by microinjection of the GABAA receptor agonist muscimol increased tail withdrawal latency. The current findings indicate that SII/Ins activity is a potential mediator of oxaliplatin-induced cold hypersensitivity.

Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS).

Cryopyrin-associated periodic syndrome (CAPS) is a rare, heterogeneous disease entity associated with NLRP3 gene mutations and increased interleukin-1 (IL-1) secretion. Early diagnosis and rapid initiation of IL-1 inhibition prevent organ damage. The aim of the study was to develop and validate diagnostic criteria for CAPS. An innovative process was followed including interdisciplinary team building, item generation: review of CAPS registries, systematic literature review, expert surveys, consensus conferences for item refinement, item reduction and weighting using 1000Minds decision software. Resulting CAPS criteria were tested in large cohorts of CAPS cases and controls using correspondence analysis. Diagnostic models were explored using sensitivity analyses. The international team included 16 experts. Systematic literature and registry review identified 33 CAPS-typical items; the consensus conferences reduced these to 14. 1000Minds exercises ranked variables based on importance for the diagnosis. Correspondence analysis determined variables consistently associated with the diagnosis of CAPS using 284 cases and 837 controls. Seven variables were significantly associated with CAPS (p<0.001). The best diagnosis model included: Raised inflammatory markers (C-reactive protein/serum amyloid A) plus ≥two of six CAPS-typical symptoms: urticaria-like rash, cold-triggered episodes, sensorineural hearing loss, musculoskeletal symptoms, chronic aseptic meningitis and skeletal abnormalities. Sensitivity was 81%, specificity 94%. It performed well for all CAPS subtypes and regardless of NLRP3 mutation. The novel approach integrated traditional methods of evidence synthesis with expert consensus, web-based decision tools and innovative statistical methods and may serve as model for other rare diseases. These criteria will enable a rapid diagnosis for children and adults with CAPS.

Síndromes periódicos asociados a criopirina: etiopatogenia, características clínicas, diagnóstico y tratamiento / Cryopiryn-associated peryodic syndrome: etiopathogenesis, clinical features, diagnosis and treatment

Los desórdenes autoinflamatorios monogénicos comprenden un grupo de enfermedades caracterizadas por episodios recurrentes y espontáneos de fiebre e inflamación sistémica, en ausencia de infección, autoanticuerpos o células T específicas para antígenos propios (autorreactivas). Estas condiciones se deben a mutaciones en genes que codifican para proteínas que son claves en la regulación de la respuesta inflamatoria innata y se consideran como inmunodeficiencias primarias. Las enfermedades que comprenden estos síndromes representan un espectro clínico de diferentes mutaciones, con ganancia de función, de un gen denominado NLRP3 o CIAS1 que codifica para la proteína criopirina, de ahí que estos desórdenes sean también conocidos con el nombre de criopirinopatías. Dentro de estos se encuentran los síndromes periódicos asociados a criopirina que incluyen tres enfermedades: el síndrome autoinflamatorio familiar inducido por frío; el síndrome de Muckle-Wells y el síndrome crónico, infantil, neurológico, cutáneo y articular. Clínicamente se caracterizan por rash tipo urticariano, fiebre periódica, inflamación a nivel del sistema nervioso central, artropatía, manifestaciones oculares y riesgo de amiloidosis como complicación a largo plazo. La función clave de la criopirina en la liberación de la IL-β sugiere el criterio racional de implementar terapias anti-IL-1 para el tratamiento de estos síndromes. La administración de drogas como anakinra, canakinumab y rilonacept muestra un efecto marcado sobre el control de las manifestaciones inflamatorias, clínicas y de los parámetros de laboratorio en estos síndromes. Se describe la etiopatogenia de estas entidades, sus principales características clínicas, el diagnóstico y el tratamiento(AU)

Monogenic autoinflammatory disorders encompass a group of diseases characterized by spontaneous and recurring fever and systemic inflammation in the absence of infection, autoantibodies or specific T cells for self antigens (self-reactive). These conditions are caused by mutations in genes encoding proteins that play a key role in the regulation of innate inflammatory response and are considered primary immunodeficiencies. Diseases comprising these syndromes represent a different clinical spectrum of mutations, with gain of function of a gene called NLRP3 or CIAS1 encoding cryopyrin protein, hence these disorders are also known under the name cryopyrinpathies. Among these are the cryopyrin-associated periodic syndrome which include three conditions: familial cold autoinflammatory syndrome; Muckle-Wells syndrome and chronic infantile neurological, cutaneous and articular syndrome. In clinical terms, it is characterized by urticarial rash, periodic fever, inflammation of central nervous system (CNS), arthropathy, ocular manifestations and risk of amyloidosis as a long-term complication. The key role of cryopirin in the release of IL-β suggests rational approach to implement anti-IL-1 therapy for the treatment of these syndromes. The administration of drugs such as anakinra, canakinumab, and rilonacept shows a marked effect on the control of inflammatory manifestations, as well as clinical and laboratory parameters in these syndromes effect. The pathogenesis of these entities, as well as their main clinical features, diagnosis and treatment are described(AU)

The preventive effect of resiniferatoxin on the development of cold hypersensitivity induced by spinal nerve ligation: involvement of TRPM8.

BACKGROUND: Resiniferatoxin (RTX) is a potent analog of capsaicin and activates transient receptor potential (TRP) vanilloid type (TRPV) 1. In the current study, we investigated the preventive effect of perineural RTX on the development of cold hypersensitivity induced by spinal nerve ligation (SNL) in rats. Furthermore, we examined the association between the expression level of TRPV1, TRP ankyrin type (TRPA) 1 and TRP melastatin type (TRPM) 8 in the dorsal root ganglion (DRG) and cold hypersensitivity after SNL. RESULTS: RTX pretreatment prevented the development of SNL-induced hypersensitivity to mechanical, thermal, and cold stimuli. Western blot analysis 4 weeks after RTX pretreatment showed that RTX pretreatment decreased the protein expression level of SNL-induced TRPM8, but not TRPV1 or TRPA1, in the DRG of SNL rats. Immunofluorescent analysis revealed that up-regulated TRPM8-stained neurons after SNL co-localized with neurofilament 200-positive neurons located in the DRG. CONCLUSIONS: Pretreatment with perineural RTX significantly inhibits SNL-induced mechanical, thermal, and cold hypersensitivity. The antinociceptive effect of perineural RTX, especially on cold hypersensitivity, may be related to the suppression of TRPM8 expression in DRG.

Evaluation of a home treatment program for cold hypersensitivity using a classical conditioning procedure in patients with hand and arm injuries.

STUDY DESIGN: Case series. INTRODUCTION: A home treatment program using a classical conditioning procedure to decrease cold hypersensitivity has potential to reduce symptoms. PURPOSE: To evaluate a home treatment program for cold hypersensitivity using a classical conditioning procedure in patients who are cold hypersensitive after hand and arm injuries. METHODS: A series of 22 patients followed a classical conditioning procedure consisting of exposing the body to cold outdoor temperatures and immersing the hands in warm water, every other day, for five weeks. The McCabe Cold Sensitivity Severity scale (CSS) was used to measure cold hypersensitivity twice before treatment, at four weeks, and at one year after treatment; Likert scales was used for the patients ratings of improvements. A cold stress test was performed to evaluate rewarming capacity in injured fingers. RESULTS: From the 20 patients, who returned questionnaires at all assessment points, 9 reported a small and three reported a moderate improvement in cold hypersensitivity after treatment. There was a trend toward improvement in the CSS (median 36; interquartile range--19 to 60) and in the rewarming pattern of fingers that were initially slow to rewarm. The improvements were sustained or increased at one-year follow-up. CONCLUSION: These preliminary results suggest that the classical conditioning procedure to treat cold hypersensitivity has potential and should be further explored in a trial with more rigorous design.

To Extinguish the Fire from Outside the Cell or to Shutdown the Gas Valve Inside? Novel Trends in Anti-Inflammatory Therapies.

Cytokines are the most important soluble mediators of inflammation. Rare pediatric diseases provided exemplar conditions to study the anti-inflammatory efficacy of new generation therapies (biologics/biopharmaceuticals) selectively targeting single cytokines. Monoclonal antibodies and recombinant proteins have revolutionized anti-inflammatory therapies in the last two decades, allowing the specific targeting of single cytokines. They are very effective in extinguishing inflammation from outside the cell, even with the risk of an excessive and prolonged immunosuppression. Small molecules can enter the cell and shutdown the valve of inflammation by directly targeting signal proteins involved in cytokine release or in response to cytokines. They are orally-administrable drugs whose dosage can be easily adjusted to obtain the desired anti-inflammatory effect. This could make these drugs more suitable for a wide range of diseases as stroke, gout, or neurological impairment, where inflammatory activation plays a pivotal role as trigger. Autoinflammatory diseases, which have previously put anti-cytokine proteins in the limelight, can again provide a valuable model to measure the real potential of small inhibitors as anti-inflammatory agents.

CAPS--pathogenesis, presentation and treatment of an autoinflammatory disease.

The cryopyrin-associated periodic syndrome (CAPS) is a severity spectrum of rare diseases. CAPS comprises the three conditions previously described as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID), also known as chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome. The clinical phenotype of CAPS is characterized by systemic inflammation. General symptoms are fatigue and fever. Local manifestations affect multiple tissues such as skin, joints, muscles, eyes, and the central nervous system. Distinct clinical features are characteristic for each subphenotype. In FCAS, these are cold-induced urticaria and fever, in MWS systemic amyloidosis and hearing loss and in NOMID/CINCA central nervous system inflammation and bone deformities. CAPS is caused by single heterozygous germline or somatic gain of function mutations in the NLRP3 gene encoding the protein cryopyrin. Cryopyrin nucleates an NLRP3 inflammasome, which regulates the activation and cleavage of caspase-1 that cleaves the pro-inflammatory cytokines, IL-1ß and IL-18. IL-1ß plays the key role in the induction of inflammation in CAPS. This has been confirmed by the application of IL-1 blocking agents, which lead not only to a rapid and sustained reversal of daily symptoms but also to some extent of long-term disease sequelae. To prevent CAPS-induced organ damage, early diagnosis and swift initiation of effective treatment are mandatory.

Glomus Tumors in the Foot: Case Series.

UNLABELLED: Glomus tumors are painful, benign neoplasms that frequently are associated with delayed diagnosis. Commonly in the hand, they rarely present in the foot. The purpose of this case series is to characterize the clinical presentation, radiology, pathology, and surgical outcomes associated with foot glomus tumors. We reviewed our pathology database for patients with foot glomus tumors diagnosed between 1995 and 2013. Medical records including physician notes, pathology, and radiology were reviewed. Eleven patients had foot glomus tumors excised at our institution during the study period. The mean age was 45.4 (range = 28-60) years. One patient was lost to follow-up. Mean follow-up for the remaining 10 patients was 44.7 (range = 3-142) months. Ten tumors were located in the subungual region, while 1 was located in the plantar pulp of the distal phalanx. All patients presented with pain. Point tenderness, cold hypersensitivity, and nail abnormalities were variably documented but frequently present. Four patients had had prior surgery for an ingrown toenail prior to presentation at our institution. Six patients had preoperative magnetic resonance imaging studies, which were diagnostic of glomus tumor in all cases except one. Radiographs failed to provide diagnosis in all 8 patients for whom they were obtained. Postoperatively, all patients had complete symptom relief with no recurrences.In conclusion, this case series demonstrates that foot glomus tumors frequently present with classic symptoms including pain, point tenderness, and cold hypersensitivity. When clinically suspected, magnetic resonance imaging should be obtained. Marginal excision results in symptom relief and cure. LEVEL OF EVIDENCE: Therapeutic, Level IV: Case series.

NLRP3 mediates osteolysis through inflammation-dependent and -independent mechanisms.

Activating-mutations in NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) cause neonatal-onset multisystem inflammatory disease. However, the ontogeny of skeletal anomalies in this disorder is poorly understood. Mice globally expressing the D301N mutation in Nlrp3 (D303N in human) model the human phenotype, including systemic inflammation and skeletal deformities. To gain insights into the skeletal manifestations, we generated mice in which the expression of D301N Nlrp3 (Nlrp3( D301N)) is restricted to myeloid cells. These mice exhibit systemic inflammation and severe osteopenia (∼ 60% lower bone mass) similar to mice globally expressing the knock-in mutation, consistent with the paradigm of innate immune-driven cryopyrinopathies. Because systemic inflammation may indirectly affect bone homeostasis, we engineered mice in which Nlrp3( D301N) is expressed specifically in osteoclasts, the cells that resorb bone. These mice also develop ∼ 50% lower bone mass due to increased osteolysis, but there is no systemic inflammation and no change in osteoclast number. Mechanistically, aside from its role in IL-1ß maturation, Nlrp3( D301N) expression enhances osteoclast bone resorbing ability through reorganization of actin cytoskeleton while promoting the degradation of poly(ADP-ribose) polymerase 1, an inhibitor of osteoclastogenesis. Thus, NLRP3 inflammasome activation is not restricted to the production of proinflammatory mediators but also leads to cytokine-autonomous responses.