Long-term persistence in patients with osteoporosis receiving denosumab in routine practice: 36-month non-interventional, observational study.

Persistence rates over 36 months with denosumab in patients diagnosed with osteoporosis in a real-world setting were examined, along with baseline patient characteristics predictive of persistence. This study represents the longest observational period with denosumab persistence and shows higher persistence rates when compared to bisphosphonates. INTRODUCTION: The study objective was to describe long-term persistence with denosumab among patients treated for osteoporosis in a real-world setting. We also sought to examine patient characteristics predictive of persistence. Lastly, this study attempted to place the results in context by conducting a literature review of published persistence data for denosumab. METHODS: This retrospective, non-interventional study analyzed 1158 patients from a specialty community private practice to assess patient persistence with denosumab in routine care. Persistence was defined as receiving seven denosumab injections, using an 8-week permissible gap, over 36 months. Non-persistent patients were further investigated retrospectively to identify reasons for discontinuation, when available. RESULTS: Demographic analysis showed a population of 1158 patients with mean age 68.4 years old and baseline T-score - 2.7; nearly half of which experienced a prior osteoporosis-related fracture. In a Kaplan-Meier survival analysis, 36-month persistence overall was 50.7%. Net persistence, as defined by receiving seven injections in the allowable time frame, was 64.2% of the cohort. In a multivariate analysis, prior vertebral fractures and recent osteoporosis therapy were associated with higher persistence; age greater than 75 years was associated with non-persistence. Reasons for discontinuation were available in 91.6% of non-persistent patients and categorized to include the ten most common explanations. CONCLUSION: This study to our knowledge represents the longest continuous observational period providing data on denosumab persistence in a real-world setting. The total persistence noted is quite robust when compared to bisphosphonates and is within the upper range of prior published studies of denosumab with shorter observation periods.

Patients with prior vertebral or hip fractures treated with teriparatide in the Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) observational study.

SUMMARY: In patients in the Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) observational study with and without a prior vertebral or hip fracture, the incidence of nonvertebral fractures was lower with >6 months of teriparatide treatment than during the first 6 months. INTRODUCTION: Clinical evidence on the effect of teriparatide in patients with prior fracture is limited. In the DANCE observational study, the incidence of nonvertebral fragility fractures (NVFX) decreased significantly in patients receiving teriparatide for >6 months (6-24 months) versus >0 to ≤6 months (reference period). METHODS: We performed a post hoc analysis to assess the effect of teriparatide 20 µg/day in patients who entered DANCE with prior vertebral or hip fractures. The incidence of patients experiencing a NVFX for four 6-month intervals during and after treatment was compared with the reference period. RESULTS: Overall, 4085 patients received ≥1 dose of teriparatide. Of 3720 with sufficient data for efficacy analysis, 692 had prior vertebral fracture, including 179 with previous kyphoplasty/vertebroplasty; 290 had prior hip fracture. These patients were older, and those with prior vertebral fractures had more comorbid conditions at baseline than those without prior vertebral fractures. The incidence of patients experiencing NVFX declined over time in all patient groups. The fracture incidence rate declined 49 and 46%, respectively, in patients with and without prior vertebral fracture and was 63 and 46% lower in patients with previous kyphoplasty/vertebroplasty and without prior vertebral fracture. NVFX declined 43 and 48% in patients with and without prior hip fracture. The reduced incidence over time was consistent in the subgroups (all interaction p values >0.05). Patients with prior fracture were more likely to experience serious adverse events. CONCLUSION: The incidence of NVFX decreased over time in patients receiving teriparatide in DANCE regardless of prior fracture status.

Successful treatment of sternal fracture nonunion with teriparatide.

SUMMARY: Fractures have a significant impact on the quality of life for the patient in addition to an enormous indirect cost in lost productivity for our economy. While majority of fractures heal uneventfully, some fail to heal even after many months resulting in nonunion. INTRODUCTION: Sternal nonunions, although rare, are particularly onerous for the patient given the magnitude of impact on quality of life. METHODS: Current treatment for fracture nonunions emphasizes various approaches to surgical fixation in addition to bone grafting. These treatments are aggressive and have a variety of drawbacks, rendering them suboptimal as a therapeutic approach. CONCLUSION: Based on the success of teriparatide in animal studies to accelerate fracture healing, there is growing interest in using this drug in humans for the same purpose. We report a case of what we believe to be the first successful use of teriparatide in the healing of a sternal nonunion fracture.

The differentiation and function of myofibroblasts is regulated by mast cell mediators.

Myofibroblasts are fibroblasts that express certain features of smooth muscle differentiation. Increased numbers of myofibroblasts and mast cells are frequently found together in a wide variety of settings, such as normal wound repair and scleroderma skin, which suggests that mediators produced by the mast cells could play a role in the regulation of myofibroblast differentiation and function. We used a human mast cell line, HMC-1, to determine if mast cells can induce normal human dermal fibroblasts to differentiate into functional myofibroblasts in vitro. We monitored the differentiation process by assaying two properties of the myofibroblast phenotype: expression of alpha-smooth muscle actin and functional capacity to contract a collagen matrix. In both a simple coculture system and in a skin-equivalent culture system, HMC-1 cells induced alpha-smooth muscle actin expression by fibroblasts. HMC-1 cells also stimulated fibroblast contraction of collagen gels, and the relative amount of contraction was dependent upon the number of HMC-1 cells present. To characterize the individual contributions made by specific mast cell products, we examined the effects of histamine, tumor necrosis factor alpha, and tryptase. Histamine induced a clear increase in alpha-smooth muscle actin expression, but it did not appear to stimulate fibroblast contraction. Tumor necrosis factor alpha had no effect in either assay. Purified human tryptase induced alpha-smooth muscle actin expression, and blocking the proteolytic activity of tryptase with specific inhibitors reduced that response. Tryptase inhibitors also eliminated the ability of HMC-1 cells to stimulate fibroblast contraction, suggesting that tryptase secreted by the HMC-1 cells may be one of the active mast cell mediators.

Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial.

OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

Sarcoidosis presenting as necrotizing sinus destruction mimicking Wegener's granulomatosis.

We describe a 26-year-old man who developed nasal stuffiness and palatal destruction. Biopsy of a mass in the ethmoid sinus confirmed sarcoidosis. Treatment was initiated with oral steroid and methotrexate, with marked improvement in his symptoms. Although paranasal sinus involvement in sarcoidosis is rare it should be considered in differential diagnosis of diseases causing palatal or paranasal sinus destruction.

Mast cell tryptase does not alter matrix metalloproteinase expression in human dermal fibroblasts: further evidence that proteolytically-active tryptase is a potent fibrogenic factor.

There is compelling in vitro and in vivo evidence to implicate mast cells in the development of fibrosis. However, an important question remains as to the mechanisms by which mast cells mediate fibrosis. Recent evidence from our laboratory (Gruber et al., 1997, J. Immunol. , 158:2310-2317) has revealed that tryptase, the unique and abundant serine protease of human mast cells, is capable of activating fibroblasts by stimulating chemotaxis, proliferation, and procollagen mRNA synthesis. Regulation of matrix metalloproteinase (MMP) expression is another key step in connective tissue remodeling. Therefore, the effect of tryptase on fibroblast MMP expression was investigated. Proteolytically active tryptase did not alter the cellular mRNA levels for fibroblast MMP-1, MMP-2, MMP-3, and MMP-9 as detected by RNase protection assays. Moreover, tryptase did not alter the basal levels of MMP-1, MMP-2, MMP-3, MMP-9, or the tissue inhibitor of MMP-1 (TIMP-1) in fibroblast conditioned media as detected by specific enzyme-linked immunosorbent assay (ELISA). These results indicate that tryptase does not increase MMP expression in normal dermal fibroblasts. Moreover, these data strengthen the potential role of this unique serine protease as a potent fibrogenic factor.

Thermal and EMG biofeedback learning in nonhuman primates.

Four monkeys were found able to learn to raise and lower hand temperature and to reduce muscle tension to low levels using feedback from the target physiological system. The establishment of this model of biofeedback learning in monkeys enables work on mechanisms mediating the modes of biofeedback most used in clinical practice. Results suggest that biofeedback learning does not need to be mediated by the type of human-specific cognitive strategies employed by humans.

Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor.

The presence of mast cells near capillary sprouting sites suggests an association between mast cells and angiogenesis. However, the role of mast cells in blood vessel development remains to be defined. In an attempt to elucidate this relationship, we investigated the effect of human mast cells (HMC-1) and their products on human dermal microvascular endothelial cell (HDMEC) tube formation. Coculture of HMC-1 with HDMEC led to a dose-response increase in the network area of vascular tube growth. Moreover, the extent of neovascularization was enhanced greatly when HMC-1 were degranulated in the presence of HDMEC. Further examination using antagonists to various mast cell products revealed a blunted response (73-88% decrease) in the area of vascular tube formation if specific inhibitors of tryptase were present. Tryptase (3 microg/ml) directly added to HDMEC caused a significant augmentation of capillary growth, which was suppressed by specific tryptase inhibitors. Tryptase also directly induced cell proliferation of HDMEC in a dose-dependent fashion (2 pM-2 nM). Our results suggest that mast cells act at sites of new vessel formation by secreting tryptase, which then functions as a potent and previously unrecognized angiogenic factor.

Isolated pulmonary microangiitis mimicking pneumonia in a patient infected with human immunodeficiency virus.

We describe the first case, to our knowledge, of apparently isolated pulmonary vasculitis mimicking bacterial pneumonia in a patient infected with human immunodeficiency virus (HIV). Patients presenting with fever, cough, and pulmonary infiltrates present a diagnostic challenge. As a result of severe T cell mediated immunosuppression and humoral dysregulation, the differential diagnosis is diverse. One must consider both noninfectious and infectious etiologies. Noninfectious etiologies such as pulmonary lymphoma, endobronchial Kaposi's sarcoma, and adverse drug reactions are common. Recent recognition of the paradoxical association between HIV and systemic vasculitis requires additional acknowledgment of this problem in diagnosis.

Human mast cells activate fibroblasts: tryptase is a fibrogenic factor stimulating collagen messenger ribonucleic acid synthesis and fibroblast chemotaxis.

The effect of human mast cells on fibroblast activity was studied using an organotypic skin-equivalent culture system. Human mast cell-1 (HMC-1) cells were embedded in a collagen gel with neonatal dermal fibroblasts at a ratio of 1:4; keratinocytes then were allowed to stratify above this composite culture. Analysis of type a1(I) procollagen mRNA synthesis by in situ hybridization revealed a substantial increase in mRNA levels in the presence of mast cells and especially following degranulation, induced by calcium ionophore A23187. Tryptase, a major product of human mast cells, could substitute for mast cells in this culture system, up-regulating procollagen mRNA synthesis. Tryptase pretreated with the specific protease inhibitor bis(5-amidino-2-benzimidazo-lyl)methane (BABIM) markedly attenuated the collagen mRNA up-regulation. Further studies revealed HMC-1 cell sonicates stimulated fibroblast chemotaxis and procollagen mRNA synthesis. Inhibition of HMC-1 sonicates with either BABIM or a neutralizing mAb against tryptase resulted in significant reduction of fibroblast chemotaxis and procollagen mRNA, implying that tryptase accounted for the majority of HMC-1 sonicate activity. Tryptase directly stimulated fibroblast chemotaxis with optimal concentrations between 10 pM and 1 nM. The maximal response of optimal concentrations of tryptase was comparable with the known fibrogenic factor, TGF-beta. Inhibition of tryptase with BABIM resulted in approximately 50% reduction in chemotactic activity. Additional studies revealed that tryptase (0.3-3 nM) stimulated procollagen mRNA synthesis in confluent monolayers of dermal fibroblasts.

Growth factors in subglottic stenosis.

We sought to define the role of fibrogenic peptides in subglottic stenosis (SGS). Biopsy specimens were obtained from patients with stenosis following endotracheal intubation (group 1, n = 5, mean age 5), patients without a history of any precedent trauma, ie. idiopathic stenosis (group 2, n = 3, mean age 40), and those without stenosis (group 3, n = 3, mean age 70). Formalin-fixed biopsy specimens were analyzed following immunohistochemical staining to determine if epidermal growth factor (EGF), platelet-derived growth factor-AA and -BB (PDGF-AA/BB), transforming growth factor-beta 1 and -beta 2 (TGF-beta 1, beta 2), or basic fibroblast growth factor (bFGF) was deposited in these tissues. Blinded analysis revealed TGF-beta 2 and PDGF-AA to be present in seven of eight biopsy specimens from SGS and absent in controls. Staining for PDGF-BB was observed in the mucosa and submucosa and occasionally within vessel walls. Staining of individual growth factors appeared to correlate closely with the presence of granulation tissue. Essentially no bFGF or TGF-beta 1 was observed. Differences were found between patients in groups 1 and 2; tissue from group 1 revealed deposition of EGF and PDGF-BB in submucosa, epithelium, and vasculature. In summary, our experimental findings implicate PDGF and TGF-beta 2, perhaps acting in concert, in mediating the pathologic fibrotic process observed in subglottic stenosis. Epidermal growth factor, in conjunction with TGF-beta and PDGF, may also have a role, but further investigation is needed to more precisely define it.

Elevated levels of 92-kd type IV collagenase (matrix metalloproteinase 9) in giant cell arteritis.

OBJECTIVE: To determine if circulating gelatinase activity and matrix metalloproteinase 9 (MMP-9) (gelatinase B, or 92-kd type IV collagenase) antigenic levels are elevated in sera of patients with giant cell arteritis (GCA), and to ascertain if MMP-9 messenger RNA (mRNA) is deposited in situ at sites of disease involvement. METHODS: Serum samples were collected from 12 patients with GCA and 12 healthy volunteers. Vascular tissue was obtained at the time of temporal artery biopsy. Type IV collagenase activity was determined by gelatin substrate zymography and the quantitative biotinylated gelatin substrate degradation assay. A double-sandwich immunoassay utilizing 2 different isotypes of monoclonal antibodies generated against MMP-9 was used for measuring serum MMP-9 antigenic levels. Finally, to localize sites of MMP-9 mRNA transcription in inflamed arteries, the method of reverse transcriptase in situ polymerase chain reaction (RTisPCR) was utilized. RESULTS: Serum gelatinase activity and MMP-9 titers were significantly increased in patients with GCA (mean +/- SEM 198.9 +/- 36.9 micrograms gelatin/hour/ml serum, versus 21.2 +/- 4.0 in controls; P = 0.0006). The differences in antigenic MMP-9 levels were even more prominent (3005.4 +/- 900.6 ng/ml and 31.6 +/- 9.8 ng/ml in GCA and control sera, respectively; P = 0.007). By RTisPCR, MMP-9 mRNA was mainly detected in cytoplasm of cells resembling smooth muscle cells and fibroblasts in regions of fragmented elastic tissue in the lamina media. CONCLUSION: Gelatinase activity, and specifically MMP-9 levels, are substantially elevated in sera of patients with GCA. Detection of MMP-9 mRNA in the lamina media of inflamed vasculature suggests that degradation of intercellular matrix, particularly elastic fibers, may play a key role in the pathogenesis of GCA. Further studies are needed to determine if the circulating MMP-9 level could be utilized as a clinical marker of disease activity.

Markedly elevated serum MMP-9 (gelatinase B) levels in rheumatoid arthritis: a potentially useful laboratory marker.

In an attempt to find a potentially useful serum marker in rheumatoid arthritis (RA) which reflects underlying pathogenic mechanisms, we measured the circulating levels of matrix-degrading metalloproteinase-9 (MMP-9), also termed gelatinase B, in sera and synovial fluid (SF) from patients with RA and also quantitated the deposition and local synthesis of MMP-9 in RA synovium. Clinical samples, subjected to gelatin substrate zymography, antigenic immunoassay, and a quantitative substrate degradation assay, revealed elevated 92- and 72-kDa proenzyme forms of MMP-9 and MMP-2 in RA sera and SF compared with healthy controls. Immunostaining on fresh RA synovial specimens revealed MMP-9 within vascular walls in fibroblast-like cells and macrophages; mRNA synthesis was detected using reverse transcriptase in situ PCR. In summary, MMP-9 levels are substantially elevated in the sera and SF from patients with RA. The RA synovium is a source of this MMP-9 production, with abundant mRNA and protein observed within several different type of rheumatoid synovial cells.

Mast cells induce T-cell adhesion to human fibroblasts by regulating intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression.

The capacity of mast cell products to mediate T-cell adhesion to fibroblasts was explored using heterotypic coculture systems or by exposing fibroblasts to mast-cell-conditioned media (MCCM), prepared by degranulating mast cells with calcium ionophore. Experimental results indicated that fibroblasts exposed to MCCM for 24 h bound fivefold more T cells than control fibroblasts. Binding was inhibited with intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1) neutralizing antibodies. Enzyme-linked immunosorbent assay and fluorescence-activated cell sorter analysis revealed that fibroblasts exposed to MCCM markedly increased ICAM-1 and VCAM-1 surface expression by 4 h, with levels maximal at 16 h and returning toward baseline by 48 h. A dose-dependent response of ICAM-1 and VCAM-1 expression was noted using serial dilutions of MCCM or by altering the ratio of degranulated mast cells cocultured with fibroblasts. Similar results were obtained using human fibroblasts derived from the dermis, synovium, and lung, although lung fibroblasts were generally less responsive. Northern analysis confirmed that MCCM regulated ICAM-1 and VCAM-1 expression at the mRNA level. In summary, mast cell products stimulated fibroblast surface expression, steady-state mRNA levels, and functional expression of ICAM-1 and VCAM-1. Experimental data suggest that mast-cell-derived tumor necrosis factor-alpha may be in large part responsible for these observations, although further studies using human mast cells will be required. Using a skin-equivalent organotypic coculture model with fibroblasts admixed with mast cells, we observed increased ICAM-1 expression in both keratinocytes and fibroblasts after activation of the mast cells.

Mast cells are potent regulators of endothelial cell adhesion molecule ICAM-1 and VCAM-1 expression.

To investigate the possible role of mast cells (MC) in regulating leukocyte adhesion to vascular endothelial cells (EC), microvascular and macrovascular EC were exposed to activated MC or MC conditioned medium (MCCM). Expression of intercellular and vascular adhesion molecules (ICAM-1 and VCAM-1) on EC was monitored. Incubation of human dermal microvascular endothelial cells (HDMEC) and human umbilical vein endothelial cells (HUVEC) with activated MC or MCCM markedly increased ICAM-1 and VCAM-1 surface expression, noted as early as 4 hr. Maximal levels were observed at 16 hr followed by a general decline over 48 hr. A dose-dependent response was noted using incremental dilutions of MCCM or by varying the number of MC in coculture with EC. At a ratio as low as 1:1,000 of MC:EC, increased ICAM-1 was observed. The ICAM-1 upregulation by MCCM was > 90% neutralized by antibody to tumor necrosis factor alpha (TNF-alpha), suggesting that MC release of this cytokine contributes significantly to inducing EC adhesiveness. VCAM-1 expression enhanced by MCCM was partly neutralized (70%) by antibody to TNF-alpha; thus other substances released by MC may contribute to VCAM-1 expression. Northern blot analysis demonstrated MCCM upregulated ICAM-1 and VCAM-1 mRNA in both HDMEC and HUVEC. To evaluate the function of MCCM-enhanced EC adhesion molecules, T cells isolated from normal human donors were used in a cell adhesion assay. T-cell binding to EC was increased significantly after exposure of EC to MCCM, and inhibited by antibodies to ICAM-1 or VCAM-1. Intradermal injection of allergen in human atopic volunteers known to develop late-phase allergic reactions led to marked expression of both ICAM-1 and VCAM-1 at 6 hr, as demonstrated by immunohistochemistry. These studies indicate that MC play a critical role in regulating the expression of EC adhesion molecules, ICAM-1 and VCAM-1, and thus augment inflammatory responses by upregulating leukocyte binding.

Angiogenic factors stimulate mast-cell migration.

Mast cells accumulate at sites of angiogenesis. The factor(s) that control mast-cell recruitment at these sites have yet to be defined. We sought to determine if angiogenic factors result in mast-cell chemotaxis. In this study, we observed that platelet-derived growth factor-AB (PDGF-AB), vascular endothelial cell growth factor (VEGF), and basic fibroblast growth factor (bFGF) each cause directed migration of murine mast cells at picomolar concentrations, with a typical bell-shaped dose-response curve. Another potent angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), appears to promote chemokinesis of mast cells, whereas tumor necrosis factor-alpha, a weak angiogenic factor, is less robust but still functions as a mast cell chemotactic factor. Epidermal growth factor (EGF), a growth factor with minimal angiogenic properties, was ineffective as a mast cell chemotactic factor. A checkerboard analysis confirmed the directional chemotactic response of PDGF-AB, VEGF, and bFGF, while indicating the chemokinetic response induced by PD-ECGF. Cross-desensitization of growth-factor-induced directed migration was observed between PDGF-AB and bFGF, and also between PDGF-AB and PD-ECGF. Tyrosine kinase-inhibitor genistein effectively dampened the chemotactic responses, whereas pertussis toxin had no effect. In summary, our findings suggest that factors known to act on endothelial cells and stimulate neovascularization may simultaneously serve to recruit mast cells to these sites. The local accumulation of mast cells is believed to facilitate new vessel formation through complex cell:cell interactions.

Murine mast cells express two types of C1q receptors that are involved in the induction of chemotaxis and chemokinesis.

Although previous studies have shown that different cells and cell lines of murine origin bind human C1q, suggesting that they display cell surface receptors for C1q, no information is available to indicate whether mouse or human mast cells express C1q receptors. This paper presents the first evidence to show that murine mast cells express specific receptors for C1q. Western blot analysis of cell membrane proteins prepared from a bone marrow-derived mouse cell line using two monospecific polyclonal Abs, one directed against the 60-kDa C1q receptor (C1q-R) that binds to the collagen-like stalk of C1q (cC1q-R) and the other directed against the 33-kDa molecule that binds to the globular "heads" of C1q (gC1q-R), show that both of these receptors are present on these cells. In addition, C1q can induce mast cell migration in a specific and dose-dependent manner. Interestingly, the C1q-induced migratory response was found to be biphasic; the first response peaked at a C1q concentration of 0.1 nM, whereas the second phase peaked at approximately 40 nM. Checkerboard analysis of the mast cell migratory response to C1q showed that the first phase was primarily due to chemotaxis and the second phase was attributable to chemokinesis. Preincubation of C1q with Abs specific for the collagen-like tail of the molecule abolished both its chemotactic and chemokinetic response, whereas heat inactivation of C1q (56 degrees C, 1 h) resulted in 85% abrogation of the chemotactic phase and 42% reduction in the chemokinetic phase. The observed mast cell migratory responses were mediated by cell surface C1q-R(s), as inclusion of a mixture of anti-C1q-R and anti-gC1q-R Abs with the cells inhibited their migratory response toward C1q. However, incubation of cells with various doses of C1q did not result in histamine release. Furthermore, engagement of mast cell C1q-Rs by the ligand C1q induced an antiproliferative response, as coculturing of mast cells with C1q resulted in a specific and dose-dependent decrease in DNA synthesis. These data suggest that C1q-Rs may play a significant role in mast cell function and regulation by providing an important signal through which mast cells can be recruited to inflammatory sites of increased C1q concentration.